Butnher Novem.OOr 3 - 4 . 2002 Symposium on
Genomiffi
and
BtotoohnolomJ
TI1e F u.tmt of Bioo1Minne m ~lemdo
!J. v~ r orkshop of' tbe POOSIHe
ABSTRAC1S
Book of Expertise
Report Generated
October 24, 2002, 12:37 pm
-
Author:
Appointment:
Campus:
School:
Department:
Campus Mail Address:
Campus Phone:
Campus Fax!
Email Address:
Web Site URl..:
Submission Date:
Accurso. Frank Full Professor
Health Sciences Center Medicine
Pediatrics
A036-8395 (Children's Hospital (303) 861 - 6181
(303) 837- 2924
accurso.frank@tchden.org
Oct 14, 2002 15:19:26
Title of Abstract: Post-Genomic Biosignatures of Childhood Lung Disease
Lung disease is the leading cause of morbidity and mortality in children. Despite intensive investigations, crucial gaps in knowledge exist even in diagnosis of childhood lung disease as well as in pathophysiology and treatment. We propose an interdisciplinary approach to development of Biosignatures of Childhood Lung Disease based on post-genomic technology.
Biosignatures will comprise genetic, genomic and proteomic profiles coordinated, through bioinformatics, with carefully defined clinical profiles. Biosignatures of disease are greatly needed for specific diagnosis and accelerated development of treatments personalized to the individual child. Recent advances in biotechnology will be used to overcome past obstacles to research in children including the need for small samples and the superposition of disease on growth and development. Improvements in proteomic and genomic analyses of small, non- invasively obtained samples provide an unparalleled opportunity for investigation of childhood disease. Bioinformatics. including data mining and pattern recognition, will elucidate the interplay among growth, development and disease. The Pediatric Pulmonary section is uniquely
positioned to provide expertise, clinical profiles and samples for these studies. Section members have national leadership positions and NIH funding in childhood lung diseases including, asthma, bronchopulmonary dysplasia, interstitial lung disease, neonatal lung disease, respiratory failure in children, pulmonary hypertension. and cystic fibrosis. Section members are nationwide leaders in cutting-edge techniques of assessing childhood lung disease including infant lung function testing, thoracic imaging, fiberoptic bronchoscopy, measurement of biomarkers of inflammation and profiling genetic modifiers of disease. Section members have access to four nationwide pediatric clinical trial networks, providing population diversity and increased potential for high-throughput. Section members consult for more than 30 biotechnology and medical firms and are familiar with needs of the private sector. Short-term commercial opportunities from this research include diagnostics for childhood lung disease (egs. bronchopulmonary dysplasia, interstitial lung disease) as well as for the elusive complications of childhood lung disease (egs.
chronic aspiration, airway reactivity). Long term opportunities include development of new treatments. Our newly formed group comprises CU faculty based at UCHSC, UCD, Children's Hospital, and National Jewish Center but samples and data will be made available to faculty throughout the CU system. Building on our current areas of strength, we will initially focus on pathways of oxidative and nitrosative injury in childhood lung disease. We plan to target an RFA from the National Institute of Child Health and Human Development titled UBiomarkers and Clinical Endpoints in Pediatric Clinical Trials'' as our first group submission.
Areas of Expertise: AREAS OF EXPERTISE ARE LISTED FOR OUR GROUP.,
Bioinformatics, Biological Instrumentation, Biomarkers of disease, Biometry, Clinical Chemistry, Clinical Pediatrics, Computational Biology, Medical devices, Oxidative stress, Proteomics
Current CU Collaborators:
Needed Expertise: Genetic Models, Genomics, Microbiology
Abstract Topic Keywords: Bioinformatics, Biomarkers, Clinical Chemistry, Computational Biology, Genomics, lung disease, Oxidative stress, Proteomics
20
Author:
Appointment:
Campus:
School:
Department:
Campus Mail Address:
Campus Phone:
Campus Fax:
Email Address:
Web Site URL:
Submission Date:
Agarwal, Rajesh Full Professor
Health Sciences Center Pharmacy
Pharmaceutical Sciences School of Pharmacy, Room 328 (303) 315- 1381
0 -
Rajesh.Agarwal@uchsc.edu
Oct 15, 2002 15:14:39
Title of Abstract: Molecular Targeting for Cancer Prevention Using Natural Products
In 2000 there were 710,000 deaths in the U.S. from heart disease while 552,000 people died
· tram
cancer. Despite reductions in age-adjusted cancer mortality rates, the absolute number of individuals dying from cancer is increasing and will surpass heart disease in coming decades due to the expanding population of older citizens and improvements in cardiac care technology.Cancer prevention may offer the best solution to this problem, however individuals are far more likely to use dietary supplements than to adopt healthy lifestyles. Understanding the molecular mechanisms behind documented supplement activity is crucial to choosing a neutraceutical type and dose. This approach is woefully missing in the expanding healthfood industry. Using silibinin as a model, we have discovered its efficacy against most epithelial cancers, both in vitro and in vivo using transplantable and transgenic tumor modefs. Its mechanism is complex, but involves inhibition of map kinases especially involving the EGF pathway, and increased apoptosis of tumor cells via inhibition of anti-apoptotic proteins. The first FDA approved clinical Phase I trial with silibinin is underway in prostate cancer patients. We now propose to expand this effort via development of a phytobiology research and training program that will combine the skills of experts in proteomics, genomics, biochemistry, bioinformatics, pharmacology, human capital organization experts and clinicians to develop effective molecular cancer prevention strategies.
Novel to our efforts will be a commitment to nearly exclusive use of clinical material (as opposed to cell lines and animal models) to test hypotheses in patients Who have or are at risk for developing cancer. Without such programs, the public will continue to 1) waste money on ineffective supplements via false marketing campaigns, and 2) not have access to truly effective agents that are well studied and understood.
Areas of Expertise: Cancer Biology, Chemical Carcinogenesis, Drug Metabolism, Pharmacology, Signal Transduction
Current CU Collaborators:
Needed Expertise: Microfluidics, Mitochondrial metabolism, Pathobiology, Protein Engineering, Protein Structure
Abstract Topic Keywords: Biolnformatics, Biological Instrumentation, Biopharmaceutics, Biotechnology, Cancer Biology, Cancer Genetics, Chemical Carcinogenesis, Genomics,
Medicinal Chemistry, Micronutrients, Molecular Biology, Nutrition, Oxidative stress, Pathobiology, Pharmacology, Proteomics, Signal Transduction, Systematic Biology, Systematics, Vitamins or Metabolic Role
22
Appointment:
Campus:
School:
Department:
Campus Mail Address:
Campus Phone:
E-mail address:
Associate Professor of Chemistry and Biochemistry Boulder
Arts & Sciences
Chemistry and Biochemistry UCB Box 215
303-315-0409
Natalie.Ahn@colorado.edu
Title of Abstract: Functional Proteomic Analysis of Signal Transduction and Disease
Authored by:
Natalie Ahn, Yukihito Kabuyama, Rebecca Schweppe, Karine Bernard, Betsy Litman, Yiqun Shellman, James Fitzpatrick, David Norris, and Katheryn Rasing
Department of Chemistry and Biochemistry, HHMI, Univ. of Colorado, Boulder, CO, and Department of Dermatology, UCHSC, Denver, CO.
Functional proteomics provides a powerful approach to screen for molecular responses at the protein level. By combining 2D-PAGE and mass spectrometry with
pharmacological strategies, molecular responses to specific signal transduction pathways can be monitored. In one application, we are identifying novel downstream targets under control of MAP kinase signaling, which reveal cellular processes not previously known to be regulated by this pathway. Importantly, targets for regulation by post-translational modification can be revealed by the approach, which complements information from DNA microarray screening. A second application Investigates synergistic interactions between signaling effectors which provide new insight into combinatorial signaling between pathways. Finally, we are using functional proteomics to monitor the protein phenotype of skin cancer progression. From this, a novel protein marker has been identified which may be clinically useful in distinguishing between nontumorigenic melanocytic nevi and tumorigenic melanoma.
Author:
Appointment:
Campus:
School:
Department:
Campus Mail Address:
Campus Phone:
Campus Fax:
Email Address:
Web Site URL:
Submission Date:
Anseth, Kristi Full Professor Boulder
Engineering and Applied Science Chemical Engineering
ECCH 111. Box 424 (303} 492- 3147 (303) 492 • 4341
kristi.anseth@colorado.edu
Oct 1, 2002 9:04:49
Title of Abstract: Engineering Synthetic Scaffolds to Control Cell Expression: Tissue Engineering Applications
Our research program is devoted to translating the basic scientific knowledge of biology, chemistry, and pharmacology at the cellular and molecular levels into the rational design and engineering of new biomaterials and devices that can benefit human health through the production of new drug delivery vehicles. matrices for engineering tissues. and degradable implants that facilitate healing. As a specific example of our approach, we are initiating new applications of genomics technology to examine differential gene expression of osteoblasts encapsulated within synthetic polymer scaffolds decorated with selected biological signals.
Through the incorporation of cell adhesion ligands and growth factors we are identifying and improving suitable polymer microenvironments which result in osteoblast gene expression most closely approximating that of osteoblasts in their native environment. The global hypothesis that we are testing is that matrix materials that promote osteoblast gene expression patterns similar to those obtained from in vivo isolated osteoblasts will provide superior performance in bone tissue engineering. Thjs research can also be extended to other types of tissue, such as aortic heart valves. A key element in tissue engineering ls to ensure that the tissue in question retains appropriate function when cultured; in developing a tissue engineered heart valve. It is important to explore whether the valve cell behavior resembles that of cells from healthy or diseased valves. This project entails not only verifying the functional state of engineered heart valve tissue, but also exploring whether we have the ability to modulate cell behavior between
diseased and healthy states via changes in scaffold material or culture conditions. Investigation of gene expression by valve cells from both healthy and diseased valves allows us.to analyze what factors contribute to the formation of diseased tissue, and enables us to develop
appropriate biomaterials and culture cohditions such that cells are not placed in a disease- promoting environment. The main challenge of this work is to define the biomimetic environment at a molecular level sufficient to provide direction in the design of improved matrices.
Areas of Expertise: Bioengineering, Biological Polymers, Tissue Engineering
Current CU Collaborators:
Needed Expertise:
Abstract Topic Keywords: Bioengineering, Biological Polymers, Tissue Engineering
24
Author:
Appointment:
Campus:
School:
Department:
Campus Mail Address:
Campus Phone:
Campus Fax:
Email Address:
Web Site URL:
Submission Date:
Artinger, Kristin Bruk Assistant Professor Health Sciences Center Dentistry
Craniofacial Biology 4200 East Ninth Ave C286 {303) 315-2920
{303) 315-3013
kristin.artinger@uchsc.edu
Oct 7, 2002 14:36:36
Title of Abstract: Cell fate determination at the neural plate border in Zebrafish
During the formation of the nervous system, neural crest cells and Rohon-Beard (RB) sensory neurons form by interactions between the neural plate and non-neural ectoderm. The neural crest is a stem cell-like population of cells that give rise to all of the peripheral nervous system, pigment cells, and craniofacial cartilage among other derivatives. The zebrafish system is an excellent model in which to study questions of neuronal development because of the extent to which we can manipulate the embryos and follow subsequent events in vivo. These types of experiments would not possible in mammals. The zebrafish embryo is completely transparent which allows us to follow labeled cells and easily manipulate gene expression at the single cell level. This coupled with the ability to do genetics makes the zebrafish system very strong for the study of development To this end, I have used the zebrafish system to identify mutations that affect formation of neural crest cells and RB sensory neurons. The zebrafrsh mutation
narrowminded{nrd), has reduced neural crest markers at the 2 somite stage, but by 24 hours, appear to have been compensated for. RB sensory neurons are completely absent, resulting in zebrafish that are insensitive to touch. Mosaic analysis has revealed that nrd acts cell
autonomously, indicating that nrd acts downstream of the neural crest inducing signal. The molecular isolation of this mutation is likely to yield an exciting r.~ew factor involved in the early neural crest cell specification. Since the zebrafish genome is currently being sequenced but not yet completed, we have used standard mapping techniques to molecularly map nrd. nrd is locate to a 600KB interval on linkage group 16 and several lead candidates, including a runt- homeodomain transcription factor, have been identified. We have knocked-down the expression of a zebrafish runt-homeodomain gene, runxb, with antisense morpholinos and shown that it has defects in the formation of RB sensory neurons. Taken together, these results suggests that nrd and runt-homeodomain factors are important factors for the formation of the cells at the neural plate border, including neural crest and RB sensory neurons. From the studies of nrd, we have determined that neural crest cells are specified early, and their formation is a multistep process, with overlapping and redundant mechanisms, that enable the formation of derivatives, even when one signaling pathway is defective.
Supported by the NIDCR K22 DE14200 and Medical Foundation, Boston
Areas of Expertise: Animal Development, Brain Development, Cell Differentiation, Cell Interactions, Developmental Biology, Developmental Genetics, Developmental Neurobiology, Molecular Biology, Neurobiology
Current CU Collaborators:
Needed Expertise:
Abstract Topic Keywords: Developmental Biology, Developmental Genetics, Developmental Neurobiology, Genetic Models, neural crest
26
Author:
Appointment:
Campus:
School:
Department:
Campus Mail Address:
Campus Phone:
Campus Fax:
Email Address:
Web Site URL:
Submission Date:
Barnes, Frank Full Professor Boulder
Engineering and Applied Science Electrical and Computer Engineer Campus Box 425
(303) 492 - 8225 (303) 492 -2758
barnes@boulder.colorado.edu Oct 9, 2002 21:46:25
Title of Abstract: EMF Modulation of Volatile Organic Compound Metabolism -A Possible Basis for Co- Carcinogenesis
EMF Modulation of Volatile Organic Compound Metabolism - A Possible Basis for Co- Carcinogenesis, Howard Wachtel, Frank Barnes,
OBJECTIVE: To explore the possibility that EMFs, from high current power lines, can modify the metabolism of carcinogenic compounds found in automotive exhaust and thereby explain the apparent co-carcinogenic effect of "high traffic density'' in combination with power line EMFs.
BACKGROUND: A Denver area epidemiological study has shown that children living near high current power lines had an elevated risk (about two fold) of developing leukemia and other childhood cancers (Savitz, Wachte~ Barnes, John and Trvdk 1988). Some subsequent studies in North America and Europe yielded similar results--but other studies did not. This dichotomy, suggested that the elevated childhood cancer risk might be due to a combination of EMF with exposures to other agents. We concluded that traffic density near the child's residence was the most likely confounder. Pearson and Wachtel,( 2000, 2001) reported that the elevated cancer risk in the Denver studies was ascribable to combined high traffic density and power line proximity--neither factor alone produced a significantly elevated risk. An implication of this finding is that the efficacy of carcinogenic automotive exhaust components--particular Volatile Organic Compounds (VOCs) is enhanced by the presence of electric or magnetic fields.
1 ,3 Butadiene (BD) is the most carcinogenic of the automotive VOCs. BD has a more potent carcinogenic effect in rats than in mice (almost 30 fold greater). In rats, the high potency is attributable to the efficiency with which BD is oxidized to its more potent carcinogenic forms, BOO and BD02. In mice, BD is predominantly broken down to harmless products. Any factor that enhances oxidation of BD and/or suppress its breakdown, could greatly enhance its carcinogenic potency. This could include the effect of electric or magnetic fields on chemical reaction rates by changing the effectiveness of the P450 enzymes in catalyzing the oxidation of BD. The question ·is whether this effect is sufficient to alter BD metabolism enough to account for a significant elevation of its carcinogenicity. The P450 enzymes are closely related to
cytochrome oxidase that has been shown to be affected by low levels of magnetic fields.
Areas of Expertise: Bioelectromagnetics, Bioengineering
Current CU Collaborators: Howard Wachtel
Needed Expertise: Bioengineering
Abstract Topic Keywords: Bioengineering, Biophysics, Cancer, Chemical Carcinogenesis, Electric and Magnetic Fields
28
Author:
Appointment:
Campus:
School:
Department:
Campus Mail Address:
Campus Phone:
Campus Fax:
Email Address:
Web Site URL:
Submission Date:
Batey, Robert Assistant Professor Boulder
Arts and Sciences
Chemistry and Biochemistry Campus Box 215
(303) 735 -2159 (303) 492 - 5894
robert.batey@colorado.edu /chemistry/bateylab
Oct 14, 2002 13:59:57
Title of Abstract: Structural analysis of RNA modifying ezymes
Almost all biological RNAs are modified at some level, most commonly by 2'-0 methylation of the ribose sugar and pseudouridylation. The importance of these modifications was recently
highlighted in the crystal structures of the 30S and 50S ribosomal subunits, which revealed that sites of RNA modification strongly clustered around the functional regions of the 16 Sand 23 S rRNA. Specific methylations around the peptidyl transferase center of the ribosomal RNA also have resulted in the widespread resistance to the macrolide antibiotics. Thus, essential modifications for translation and modifications involved in resistance mechanisms are attractive targets for development of new antibiotic agents. To understand how various methylating enzymes specifically recognize their rRNA and tRNA targets, we are pursuing structural analysis of various RNA-protein complexes by X-ray crystallography. In archaea and eukarya, 2'-0 methylation of rRNA is catalyzed by the Box C/0 small nucleolar (sno) RNP. This enzyme consists of three proteins, one of which is the methyltransferase, and a single snoRNA that contains an element that base pairs to the rRNA to determine the site of methylation. We are currently working on engineering a model snoRNP complex using components from the archaean P. horikoshii for detailed mechanistic and structural studies. These studies are being complimented by worK on several bacterial RNA methyltransferases, which consist of only a single protein. For each of these projects we seek to determine structures of the RNP
complexes with substrate bound, complimented by biochemical studies focusing on enzymatic catalysis and substrate recognition. Another of our crystallographic projects is to determine the structure of an essential modifying enzyme tadA, which deamidates the wobble position adenosine within the anticodon loop of tRNA-Arg. To compliment our structural analysis of modifying enzyme-RNA complexes, we also seek identify the enzymes that are responsible for known modification and assess their importance on E. coli viability. We would like to develop novel RNA-based pull-down assays to search for interacting proteins by coupling hexahistidine tags and FLAG tags to the 3' end of an RNA of interest and exploiting existing methodologies for the purification and identification of the proteins. This approach should be generally applicable to the identification of ligands, proteins or nucleic acids that bind to any given RNA target.
Areas of Expertise: Molecular Biology, Protein Structure, Protein Synthesis, RNA, Structural Biolqgy
Current CU Collaborators:
Needed Expertise: Antimicrobial Resistance, Bacteriology, Bioinformatics, Cell Biology, RNA
Abstract Topic Keywords: antibiotic resistance, RNA, Structural Biology, X-ray crystallography
30
Author:
Appointment:
Campus:
School:
Department:
Campus Mail Address:
Campus Phone:
Campus Fax:
Email Address:
Web Site URL:
Submission Date:
Bekoff. Anne Full Professor Boulder
Arts and Sciences
Environmental, Population, and 0 Dept of EPO-Biology, CB334 (303) 492 - 5114
0 -
Anne .Bekoff@colorado.edu
Oct 15, 2002 14:53:41
Title of Abstract: Embryonic Administration of Pyridoxine Selectively Kills trkC Immunoreactive Neurons in the DRG
High doses of pyridoxine, vitamin 86, have been shown to selectively kill proprioceptive sensory neurons in the DRG of adult mammals (Antropol and Tarlov, J. Neuropathol. Exp. Neural., 1942).
We have previously shown that embryonic administration of pyridoxine to chicks can alter embryonic and post-hatch motor behaviors (Sharp et al., Soc. Neurosci. Abstr., 1998). The purpose of the present study was to determine if high doses of pyridoxine cause a selective loss of proprioceptive neurons in the chick.
Pyridoxine (3.75 mg in 100 ml of saline) was injected into eggs on embryonic day (E) 7 and E8.
We have previously shown that this treatment causes reduction of the amplitude of leg movements recorded on E9. Nissl staining of E9 spinal columns reveals an apparent loss of large neurons in the DRG with clear nuclear profiles, but no apparent alteration of morphology in the spinal cord. The number of trkC immunoreactive neurons in the DRG of E13 embryos was reduced by more than 85%. There was no loss of spinal motor neurons or trkC negative neurons in the DRG. However the volume of the spinal cord was greatly reduced. Neither the ventral nor lateral white matter was reduced in area. However, the dorsal white matter and the spinal gray matfer appear to have lost fiber volume. These results are consistent with the selective loss of proprioceptive neurons in the chick DRG subsequent to pyridoxine application. It remains to be demonstrated whether the reduction in spinal volume is merely due to the loss of proprioceptive processes or if there are further rearrangements due to the loss of proprioceptive input.
We are interested in developing techniques for recording neuronal and motor activity during development. These goals are particularly rigorous due to the size and environment of
embryonic organisms. Additionally, we would like to work towards developing implants that could provide feedback to an organism such as the proprioceptive information lost by the animals described in this abstract. Supported by NIH Grant HD39241 to AAS.
Areas of Expertise: Developmental Biology, Developmental Neurobiology, Electrophysiology, Kinesiology, Muscle Structure or Function, Neurobiology, Sensory Physiology, Vertebrate Physiology
Current CU Collaborators:
Needed Expertise: Bioengineering, Biological micro/nano electro-mechanical systems (BioMEMS), Biosensors
Abstract Topic Keywords: Animal Development, Developmental Biology, Developmental Neurobiology, Kinesiology, Muscle Structure or Function, Neurobiology, Sensory Physiology.
Vertebrate Physiology
32
Author.
Appointment:
Campus:
Sch.ool:
Department:
Campus Mail Address:
Campus Phone:
Campus Fax:
Email Address:
Web Sitec URL:
Submission Date:
Bemis, Lynne Assistant Professor Health Sciences Center Medicine
Medical Oncology 8-171 BRB532 (303) 315- 4755 (303) 315 - 8825
Lynne.Bemis@uchsc.edu
Oct 14, 2002 20:21:18
Title of Abstract: Genetic Education for Community Members and Students
The planning committee for the Human Genome project realized that the information gained from sequencing the entire human genome would have far reaching implications for humanity. In order to address these issues proactively, The Ethical, Legal, and Social Implications (ELSI}
Research Program was established. In the post-genome sequencing era, ELSI continues to be an integral component of the Human Genome project. Genetic Education for Native Americans (GENA) has been funded by the ELSI program (NHGRl R25HG01866) since 1998 to develop an educational program covering the basic science of genetics, cultural implications and ethical considerations of the genome project.
The goals of GENA were established based on community needs expressed at focus groups and during individual meetings with community members. Elders from the community expressed the need for information about genetic testing and research so that rnformed decisions about healthcare could be made. In addition, elders expressed the need for trained scientists and healthcare professionals from their own communities to be the providers of genetic information.
Thus, the primary goal of GENA is to provide culturally competent education about genetic research and genetic testing to Native American college and university students. The secondary goal is to increase the number of Native people who have access to scientific mentoring
experiences in genetic counseling, genetic research and careers. The GENA curriculum has been implemented by Dr.s Bemis and Burhansstipanov at over 20 professional meetings with over 500 participants from 1998 through 2002. Participants have included undergraduate and graduate students, community and faculty members. GENA is team taught with a cultural representative as well as instructors from the fields of public health, molecular genetics, or classical genetics as part of each presentation. The team approach has been extremely successful as evaluated by pre- and post-tests, from 90% of all participants, as well as delayed assessment from 10% of participants. Assessments comparing the increased knowledge post- education as compared to pre-education have revealed a gain of knowledge for all workshops where GENA has been presented. The overall level of interest in information pertaining to the 11uman genome has been rated as extremely high in this medically underserved community.
Requests for additional education programs about the human genome and specifically designed for medically underserved communities continue to be received by the GENA staff and will be developed in the future.
Areas of Expertise: Cancer Biology, Cancer Genetics, Community Education Programs, Molecular Biology
Current CU Collaborators: Bill Robinson, Paul Spicer, Robert Winn, Wayne Zundel, Wilbur Franklin
Needed Expertise: Bioinformatics, Community Education, Drug Metabolism, lmmunodiagnostic, Lab on a chip
Abstract Topic Keywords: Cancer Genetics. ELSI
34
Author:
Appointment:
Campus:
School:
Department:
Campus Mail Address:
Campus Phone:
Campus Fax:
Email Address:
Web Site URL:
Submission Date:
Bentley, David Full Professor
Health Sciences Center Medicine
Biochemistry and Molecular Genet 8121
(303) 315-5518 (303) 315-8215
david.bentley@UCHSC.edu
Oct 15, 2002 14:32:33
Title of Abstract: A genome wide approach to mRNA capping
The cap 7MethyiGpppN is a signature motif at the 5' end of all messenger RNA molecules. The cap functions as an identity tag which promotes splicing and 3' end processing of mRNA
precursors in the nucleus, and translation of the mature mRNA in the cytoplasm. Removal of the cap is important for signalling the end of a mRNA's life prior to its degradation. The dogma in text books is that all mRNA's in the cell have a cap that is put on all transcripts made by RNA
polymerase II at a very early stage when the transcript is only 25-50 bases long. Our lab has shown that the capping enzymes actually bind specifically to the phosphorylated C-terminal domain {CTD) the largest RNA polymerase II subunit both in vitro and in vivo. This observation suggested to us that signals which affect phosphorylation of the CTD could influence capping by affecting· recruitment of capping enzymes. In support of this idea we have shown that certain transcription factors can not only stimulate the amount of RNA made from a gene but also the extent to which those RNA's are capped. The possibility that capping is not a constitutive feature of all mRNA's but rather that the extent of capping can be regulated has important implications for the expression of all genes. We have initiated a project In budding yeast to measure the extent of capping of all mRNA's using a micro-array with all 6200 yeast genes. The microarrays are hybridized to RNA that has been fractionated into capped and uncapped populations by binding to the cap binding protein eiF4E. Our initial results show that, contrary to expectation, there is not a vast excess of capped over uncapped transcripts for all genes. Instead we find a wide spectrum of capped: uncapped mRNA's for different genes. In future, we wish to pursue these results in yeast mutants that affect capping and decapping and to extend these studies to the human cells
Areas of Expertise: Gene expression, Molecular Biology, RNA
Current CU Collaborators:
Needed Expertise: Bioinformatics, Genomics
Abstract Topic Keywords: Genomics, Molecular Biology, RNA
._ .
._.
... -
Author:
Appointment:
Campus:
School:
Department:
Campus Mail Address:
Campus Phone:
Campus Fax:
Email Address:
Web Site URL:
Submission Date:
Betterton, Meredith Assistant Professor Boulder
Arts and Sciences Applied Mathematics 526 UCB
(303) 492 - 4668 (303) 492 - 4066
Meredith.Betterton@colorado.ed http://www .math. nyu.edu/-mdb/
Oct 7, 2002 13:50:55
Title of Abstract: Helicase opening of duplex DNA: active versus passive opening
In cells, proteins called helicases open double-stranded nucleic. acid (NA) molecules such as DNA. Such helicase proteins play an important role in cellular processes (such as DNA copying and repair) which access double-stranded NA; in addition, mutations to helicases are involved in human genetic diseases associated with a predisposition to cancer. Despite extensive structural and biochemical studies of helicases, relatively little theoretical work has addressed helicase mechanism. In my opinion, a full understanding of how helicases function (and what happens when they malfunction) requires an integration of structural and biochemical work with theoretical and computational modeling.
I have developed a biophysical model of nucleic acid opening by helicases (with a focus on monomeric helicases as a starting point), and have chosen to focus on the question of "active"
versus "passive" opening. Helicase opening of double-stranded NA is often classified as either active (the helicase directly destabilizes the dsNA to promote opening) or passive (the helicase binds ssNA available due to a thermal fluctuation which opens part of the dsNA). In this work, I will present a "hopping" model of helicase opening of dsNA, based on helicases which bind single NA strands and move towards the double-stranded region. Consider two degrees of freedom: the position of the helicase, and the position of the junction between single-stranded and double-stranded NA. 1 propose that the helicase and the nucleic acid ss-ds junction interact with each other via a potential which depends on their separation along the NA chain. The form of the potential determines whether the opening is active or passive. One can calculate the rate of passive opening for one type of helicase, called PcrA, and show that the rate increases when the opening is active. Finally, I consider how to choose the interaction potential to optimize the rate of strand separation. One important result is the finding that active opening can increase the unwinding rate significantly compared to passive opening.
Areas of Expertise: Biological Polymers, Biophysics, DNA Repair, DNA Replication, DNA- enzyme interactions, Microtluidics
Current CU Collaborators: Thomas Perkins
Needed Expertise: Bioengineering, Bioinformatics, Biological Adaptation, Biological micro/nano electro-mechanical systems (BioMEMS), Biological Polymers, Biophysics, Biotechnology, Cancer Biology, Cell Biology, Cell Interactions, Computational Biology, DNA Repair, DNA Replication, Genomics, Microfluidics, Molecular Biology, Nano-composites, Physical Biology, Protein Engineering, Protein Structure, Proteomics, RNA, Structural Biology
Abstract Topic Keywords: Biophysics, DNA Repair, DNA Replication, DNA-enzyme interactions, helicases, theoretical models
37
Author:
Appointment:
Campus:
School:
Departmen1:
Campus Mail Address:
Campus Phone:
Campus Fax:
Email Address:
Web Site URL:
Submission Date:
Bialasiewicz, Jan Associate Professor Denver
Engineering and Applied Science Electrical Engineering
Box 110
(303) 556 - 4333
0 -
jan.bialasiewicz@cudenver.edu
Sep 27,2002 21:27:21
Title of Abstract: Wavelet~Based Medical/mage Processing for Early Detection of Cancer
In this research, we look for signatures of cancer in various medical images through their
analysis using wavelets. In particular, wavelet analysis is applied to differentiate between healthy and malignant tissues by decomposing the image into an approximation and several levels of details and then reconstructing the images from details that are modified to enhance texture differences.
We plan to test our algorithms using medical images with known classification and we already have some preHminary results in wavelet-based analysis of CT scans of malignant tissues that will be shown in this presentation.
Our overall objective is to deliver a theory and software, which would support the development of technologies that integrate the following capabilities:
·Highly specific recognition capabilities for the components of the signature;
·Recognition-dependent direct signal generation;
·Signal capture and interpretation tools (e.g., mathematical approaches to feature definition and
extraction) for the investigator or clinician; ·
·Intervention (treatment, prevention) delivery to the site of signal detection;
·Monitoring the effectiveness of intervention.
Below we give a basic introduction to the elements of wavelet analysis used in our research.
A wavelet is a function of zero average, which is dilated with a scale parameter. There is a scaling function associated with a wavelet. In wavelet analysis, we convolve a scaling function and a wavelet with the rows and columns of the image to create wavelet transforms.
The result of convolving the scaling function with image is an approximation image. The subsequent convolving of the approximation image with the wavelet creates the wavelet transform. The convolution with the rows of the image gives the horizontal details and the convolution with the columns creates the vertical details of the images.
A direction image can be created, which shows the direction of fastest descent for the pixel intensities by calculating the gradient of the images.
The edges of structures in images can be used to develop a signature characterizing the tissue.
The discrimination of edges versus texture depends on the scale of analysis. The detection of edges can be realized by detecting modulus maxima in a two-dimensional dyadic wavelet transform. The modulus maxima of the image can be created by finding the square root of the sum of the squares of the vertical and horizontal details. The Lipcshitz regularity of edge points, derived from the decay of wavelet modulus maxima across scales, can be used to differentiate tissues.
Areas of Expertise: dynamic system modeling and identification., pattern recognition, Signal Transduction, Wavelet theory and applications, wavelet-based signal processing
Current CU Collaborators: Francis Newman (HSC), Fred Kolhouse (HSC)
Needed Expertise: Oncology, Radiology
Abstract Topic Keywords: Early Detection of Cancer, Medical Image Processing, Medical lnfonnatics, Wavelet Analysis
39
Author:
Appointment:
Campus:
School:
Department;
Campus Mail Address:
Campus Phone:
Campus Fax:
Email Address:
Web Site URL:
Submission Date:
Billups, Stephen Associate Professor Denver
Arts and Sciences Mathematics Box 170
(303) 315- 7950 (303) 556 - 8550
sbillups@carbon .cudenver.edu www-math.cudenver.edu/-billups Oct 1. 2002 1 0:09:54
Title of Abstract: Cluster Gene Expression Data Via Independent Component Analysis
A method is presented for clustering gene expression microarray data using independent component analysis. In this method, data are grouped into clusters, each of which is modeled as a mixture of statistically independent components coming from a number of sources. It is hypothesized that such a method will be useful in analyzing gene expression data since at least some of the differences in gene expression may be due to a small number of essentially independent mechanisms. The method also allows the inherent dimensionality of each cluster to be identified automatically.
To make the method computationally tractable, a variational
Bayesian method is applied to approximate the posterior probability density functions of the model parameters.
Areas of Expertise: Bioinformatics. Computational Biology, data mining. machine learning
Current CU Collaborators: Larry Hunter, UCHSC Dept. of Pharmacology
Needed Expertise: Bioinformatics, Computational Biology, Drug Metabolism, Genetic Models, Genomics. Medical Informatics. Metabolic Biology. Pharmacogenetics, Protein Structure, Proteomics
Abstract Topic Keywords: Bioinformatics, clustering. Computational Biology, gene expression, independent component analysis, variational learning
_,
-
Author:
Appointment:
Campus:
School:
Department:
Campus Mail Address:
Campus Phone:
Campus Fax:
Email Address:
Web Site URL:
Submission Date:
Blumenthal, Tom Full Professor
Health Sciences Center Medicine
Biochemistry and Molecular Genet B-121
(303) 315-8181 (303) 315- 8215
tom.blumenthal@uchsc.edu uchsc.edu/sm/bbgn/blumenthal2.
Sep 20,2002 14:50:38
Title of Abstract: C. elegans operons: A novel tool to find functionally related genes
C. elegans and its relatives are unique among animals in having polycistronic transcription units,
much like bacterial operons. These operons may constitute an important gene finding tool. We have performed microarray analysis of theC. elegans genome to determine which genes are contained in operons (Blumenthal et al., 2002, Nature 417:851). Surprisingly, >15% of C.
elegans genes are in operons ranging from 2 to 8 genes long. We have analyzed the list of -1000 operons, containing -2,600 genes, to determine what types of genes they contain and,· importantly, to what extent functionally-related genes are co-transcribed in operons.
Whereas some classes of genes are highly represented in operons, others are almost never in operons, suggesting operons are not random gene assemblages. For example, -50% of genes whose products are destined for the mitochondria are transcribed in operons. Similarly, -50% of genes for the basic transcription, splicing and translation machinery are in operons. In contrast, transcription factor genes are virtually never in operons. Also, genes that are highly regulated in a particular tissue are generally excluded from operons, including collagens, sperm proteins, intermediate filament proteins, cytochrome P450s, immunoglobulin domain proteins and
basement membrane proteins, It appears that proteins are made in operons if they are either not regulated or are regulated in response to global signals.
Many of the C. elegans operons do not appear to make functional sense. On the other hand, many others do. There are numerous operons that contain more than one gene encoding proteins that are part of the basic transcription machinery, and this occurs far more often than would be expected by chance. This is also true of the splicing machinery and of mitochondrial proteins. Furthermore, there are operons that contain a subunit of one of the RNA polymerases and one of the basic factors that act with that polymerase. The operon list suggests many unsuspected relationships among proteins, but whether most operons involve functionally related genes is not yet known. Many homologs of human disease genes are contained in operons, and determining whether the products of the other genes in these operons are related proteins is worth investigating.
Areas of Expertise: RNA
Current CU Collaborators: John Hutton
Needed Expertise:
Abstract Topic Keywords: RNA
42
Author:
Appointment:
Campus:
School:
Department:
Campus Mail Address:
Campus Phone:
Campus Fax:
Email Address:
Web Site URL:
Submission Date:
Bodine, Cathy Assistant Professor Health Sciences Center Medicine
Physical Medicine & Rehabilita
C230~uchsc
(303) 315- 1281 (303) 837- 1208
cathy.bodine@uchsc.edu www.uchsc.edu/atp Oct 15, 2002 15:37:43
Title of Abstract: Etiology based memory support systems: Developing a new paradigm
Challenges to human memory and executive function arise from manifold causes- genetic, in- utero and post-utero, and acquired conditions such as traumatic brain injury as well as
decreased cognitive function associated with aging, and diseases such as multiple sclerosis and Alzheimers. Interventions and support devices for memory loss and executive function have traditionally been designed without careful consideration of etiology (causes). Etiology has helped inform specific human interventions but not assistive device design.
Compounding the lack of a unified approach to assistive device design and intervention is the paucity of specific outcomes research in the entire field of assistive technology device and intervention systems.
Our long-term goal is to develop an integrated paradigm that includes etiology, technology, and social/intervention systems to inform the design and delivery of the next generation of assistive technologies and intervention strategies for memory and executive function support. In addition, we think this model offers a new approach to a wide range of supports and interventions for other cognitive disabilities.
Our strategy begins with a detailed meta-analysis of the literature:
<sum> medical (etiology-based and pharmacological supports)
<sum> technology (both durable medical and off-the-shelf technologies) and
<sum> social system/interventions (clinical interventions, social supports).
This meta-analysis will identify those areas where etiology specific approaches can inform future device design and intervention strategies. The results of this research, combined with using the latest modular, personalizable hardware and software technologies, wilt set the stage for a new paradigm in memory and executive function support systems and clinical interventions.
The strategy of carefully matching etiology, rather than simply functional characteristics, in designing personalized interventions, assessment tools and support devices is new and offers a more informed and integrated approach than those currently available. As we develop this framework we will apply it to a number of other cognitive disabilities. At the end of the first phase of the research we will generate a set of NIH/NICHD/NIDRR proposals to pilot the design (R21)
and measure the clinical and technical outcomes of a set of new memory and executive function support devices and interventions. This will lead to a proposal for an NIH phase three clinical trial (R01).
An exciting component of this work is the collaboration between several departments at the Health Science Center and several departments on the Boulder campus.
Areas of Expertise: assistive technology, Brain Development, Brain Injury, Gerontology, Medical devices, outcomes measurement, project management, speech~Janguage pathology
Current CU Collaborators: Michael Lightner
Needed Expertise: Behavioral Medicine, Biostatistician, Developmental Neurobiology
Abstract Topic Keywords: assistive technology, Bioengineering, Biotechnology, Brain Development, Brain Injury, cognitive disabilities, executive functions, Gerontology, Medical devices, memory systems, outcomes research
44
Author:
Appointment:
Campus:
School:
Department:
Campus Mail Address:
Campus Phone:
Campus Fax:
Emaif Address:
Web Site URL:
Submission Date:
Bowler, Russell Assistant Professor Health Sciences Center Medicine
Medicine
1400 Jackson Street, K736a (303) 388- 1801
(303) 270 -2249 BowlerR@njc.org
Oct 9, 2002 12:28:07
Title of Abstract: Genomic and proteomic approaches to identifying responses to oxidative stress
Oxidative stress is defined as an imbalance between reactive OXYgen species and antioxidants.
Reactive oxygen species include toxic molecules such as superoxide, hydrogen peroxide, and hydroxyl radical. Antioxidants include both low molecular weight compounds such as vitamin C and E' as well as enzymes such as superoxide dismutase (SOD) and catalase. In many diseases such as stroke, asthma, and acute respiratory distress syndrome (ARDS), oxidative stress contributes to dysfunction and injury of normal tissues. We have recently used microarray analysis to show that administration of SOD mimetics may protect the brain during ischemia and reperflJsion by attenuating upregulation of inflammatory genes such as interleukin-6 (Free Radical Biology and Medicine 2002, 33 (8):1021-1166). An ongoing analysis of the proteome will be used to detennine whether there is a correlation between gene expression and protein expression in this model. We are also using proteomics to determine how lung epithelial lining fluid (ELF) proteins are modified in ARDS. Prelinary results suggest that the majority of ELF proteins 'in ARDS patients are derived from serum; however, we find that the ELF proteome is distinct from the serum proteome, suggesting that additional post-translational modifications are occuring in the lung. Finally, we have found that mice deficient in extracellular SOD have altered airway reactivity. We are currently using microarray analysis to determine how extracellular SOD deficiency might account for this phenotype.
Areas of Expertise: Cell Biology, Oxidative stress
Curi"ent CU Collaborators: Brian Day, James Crapo, Ling-Yi Chang, Mark Duncan, Scott Worthen
Needed Expertise: Bioinformatics, Cancer Biology, Computational Biology, Genomics, lmmunobio!ogy
Abstract Topic Keywords: Biomimetics, Brain Injury, Cardiovascular Biology and Physiology, Genomics, Oxidative stress, Proteomics
-
- -
- -
Author:
Appointment:
Campus:
School:
Department:
Campus Mail Address:
Campus Phone:
Campus Fax;
Email Address:
Web Site URL:
Submission Date:
Bowman, Christopher Full Professor
Boulder
Engineering and Applied Science Chemical Engineering
CB 424, ECCH 136 UC-Boulder (303) 492- 3247
(303) 492- 4341
bowmanc@colorado.edu
Oct 1, 2002 15:45:04
Title of Abstract: 30 Polymeric Microfluidic Devices
Significant academic and industrial investment has been devoted to fabrication strategies for "lab- on-a-chip" devices (micro total analysis systems, mTAS) that perform analytical tasks such as detection of biological and chemical hazards, point-of-care medical diagnostics, or other common biological and chemical separations and analyses. The demands on these devices are very high.
They must be durable and inexpensive, yet provide an accurate and rapid analytical response.
Most microfluldic devices are fabricated in silicon or glass with micromachining technology.
However, these substrates exhibit undesirable bulk properties and have limited available surface modification methods, which reduce their effectiveness.
The method proposed in this poster allows for use of a wide variety of photopolymerizing systems in the fabrication of microfluidic devices. Furthermore, all surfaces of the device are readily surface modifiable using living radical photopolymerization (LRPP) and vinyl containing monomers. Using LRPP chemistries, hydrophilic and hydrophobic regions within the channels are useful for fluid control and detection schemes involving surface anchored antigen labeled compounds.
The spatial resolution is controlled with micromanipulators yielding structures well within the microfluidics range (100 mm in the normal plane and a minimum of 10 mm layer thickness).
Three-dimensional devices with covalently bonded layers are made possible through the use of sacrificial layers, enabling novel geometries and functions especially suited for separation of biologically interesting compounds. Through the addition of patterned functionalities such as proteins or peptide sequences to the surface of these devices, a plethora of applications can be explored and will have an interdisciplinary impact on many areas of research.
Areas of Expertise: Microfluidics
Current CU Collaborators: Bobby Sebra, Brian Good, Brian Hutchison, Christopher Brotherton, Microfluidics: Kristi Anseth, Rob Davis, Sirish Reddy, Tommy Haraldsson
Needed Expertise: Microfluidics
Abstract Topic Keywords: BioMEMs, Living Radical Polymerization. Microfluidics,
Photopotymerizations
47
Author:
Appointment:
Campus:
School:
Department:
Campus Mail Address:
Campus Phone:
Campus Fax:
Email Address:
Web Site URL:
Submission Date:
Briggs, Bill Full Professor Denver
Arts and Sciences Mathematics Box 170
(303) 556 -4809 (303) 556 - 8550
wbriggs@math.cudenver.edu www-math.cudenver.edu/-wbriggs Oct 11, 2002 13:46:49
Title of Abstract: Mathematical Models in Molecular Biology
see Harvey Greenberg
Areas of Expertise: Bioinformatics, Genetic Models, Mathematical modeling
Current CU Collaborators: Harvey Greenberg, Mike Grant
Needed Expertise: Bioinformatics, Genetic Models, I am open to collaboration.
Abstract Topic Keywords: Molecular Biology
_ ..
-·
. -
Author:
Appointment:
Campus:
School:
Department:
Campus Mail Address:
Campus Phone:
Campus Fax:
Email Address:
Web Site URL:
Submission Date:
Carlson, Robert Full Professor Colorado Springs
Engineering and Applied Science Mathematics
Department of Mathematics (719) 262- 3311
(719) 262 - 3605 carlson@math.uccs.edu
Oct 14, 2002 14:25:13
Title of Abstract: Mathematical models and genetic manipulation for signaling pathway investigation in yeast
Mathematical models and genetic manipulation for signaling pathway investigation in yeast Robert Carlson, James Mattoon, Jugal Kalita
The regulated transport of molecules across semi-permeable membranes is ubiquitous in living organisms, ranging from bacteria to humans. The processes exhibit a high level of chemical specificity that depends upon enzyme-like transporter proteins called permeases. These proteins are located within the membranes of cells and intracellular structures. The numbers of permeases in membranes depend upon the controlled expression of members of the associated gene set The regulation of this expression is predominantly transcriptional. This involves transcription factors, proteins that associate with the DNA of specific permease genes to enhance or inhibit their transcription by RNA polymerase to produce messenger RNAs. The transcription factors in tum respond directly or indirectly to concentrations of one or more
biochemicals in the extracellular or intracellular environment of the cell. Commonly, extracellular signals originate at protein receptors in the cell membrane that interact directly with specific biomolecules at the cell surface. This interaction initiates a cascade of reactions which proceeds through the cell cytoplasm. terminating when there is a reaction with a transcription factor.
Several such signaling pathways have been discovered, but only a few of them are well understood.
In this project we will investigate a recently discovered signaling pathway in the yeast Saccharomyces cerevisiae. This system permits the cell to sense the presence of significant concentrations of extracellular amino acids and to transmit this information to permease genes in the nucleus, thereby initiating production of new amino acid permeases destined for the cell membrane.
Yeast provides an excellent model for such a study. Although unicellular, it is a eukaryote.
organized in essentially the same way as multicellular oranisms, including humans. It grows rapidly and is easily manipulated genetically. The entire yeast genome of 6200 genes has been sequenced. Notwithstanding this large knowledge base, signaling is not well understood, even in yeast.
We plan to utilize biological knowledge, genetic manipulation, and computer/mathematical modeling in an iterative process to study and validate models of signaling within yeast, and to suggest additional biological experiments to test this understanding and the corresponding models. The main issues include the following: signaling site enumeration, signal initiation, signal transport process and timing, genetic response mechanisms, protein synthesis and transport, incorporation of permeases into cell membranes, and signal termination.
Areas of Expertise: Computational Biology, Computer Simulations, Differential Equations.
Mathematical Modeling, Signal Processing
Current CU Collaborators: James Matttoon, Jugal Kalita
Needed Expertise:
Abstract Topic Keywords: Cell Biology, Computational Biology, Membrane Transport, Molecular Biology
50
Author:
Appointment:
Campus:
School:
Department:
Campus Mail Address:
Campus Phone:
Campus Fax:
Email Address:
Web Site URL:
Submission Date:
Carr, Steve
Assistant Professor Boulder
Arts and Sciences
Molecular, Cellular, and Develop 347 UCB
(303) 492 - 587 4 (303) 492-7744
carr@stripe.colorado.edu
Oct 2, 2002 12:06:34
Title of Abstract: Shared Facilities of MCDB
Shared Facilities of MCDB
The Department of Molecular, Cellular, and Developmental Biology on the Boulder Campus of the University of Colorado has a long history of co~perative research. Keith Porter started the tradition in the early 70's with a 1 million·volt electron microscope, which has brought
researchers from around the world to the Department. Currently the Department is setting up an Affymetrix microchip facility. MCDB has worked hard to provide access, to many high priced pieces of equipment, for researchers both in the Department as well as collaborators from outside the University. The Facilities now available to all Department members include:
Conventional and Transgenic animal facilities; DNA Sequencing; high, intermediate and normal voltage electron Microscopes with sample preparation facilities; Microchip array system;
Biovisual facility with Confocal microscope, phosphorimager, X-Omat film processor, and color laser printer. as well as building wide de-Ionized/distilled water, autoclaves and sterilizing ovens.
Funding for these facilities has been quite varied including grants. indirect cost recovery, and user fees. The department is currently finishing a $17 million remodel of Porter Biosciences that will bring the building up to the standards of the new MCDB addition, which was finished in 1995.
The 2 buildings together contain 125,000 square feet of useable (net) space. When the project is finished this January 2003, the department will have space available for new faculty and more collaborations.
Areas of Expertise: Building Management, Molecular Biology, Molecular Genetics
Current CU Collaborators: The Department of MCDB
Needed Expertise:
Abstract Topic Keywords: Developmental Biology, Genomics, Molecular Biology
-·
-·
-
Author:
Appointment:
Campus:- School:
Department:
Campus Mail Address:
Campus Phone:
Campus Fax:
Email Address:
Web Site URL:
Submission Date:
Choi, Min-Hyung Assistant Professor Denver
Engineering and Applied Science Computer Science
Campus Box 109, PO Box 173364 (303) 556 -8425
0 -
mchoi@carbon.cudenver.edu www.cudenver.edu/-mchoi Oct 1, 2002 23:29:26
Title of Abstract: Constraint-based Adaptive Simulation of Deformable Objects
This abstract describes robust and effective techniques to model, simulate and interact with deformable objects. The physical modeling of deformable objects is one of the fundamental and crucial components of many medical and bioinformatics visualization application providing an effective way to display and interact with virtual objects that better represent true physical nature, beyond unrealistic rigid-body approximation. Deformation modeling has been studied extensively using both discrete models and continuum mechanics-based models. However, two major issues still pose a significant challenge. First, the conflicting demand between computational efficiency and biomechanical realism directs us to take trade-offs or to sacrifice one for the other. To be applied in real-time applications, especially to achieve a haptic rate force feedback,
biomechanical realism has been compromised by adopting linear elasticity with many simplifications and approximations. Second, the robust treatment of interaction between soft objects and intuitive control is often overlooked, being represented by a single point of contact or given external forces. However, many anatomical and cell structures involve complex interaction between multiple soft tissue structures. Their complex interplay generates multiple collision points and contact areas, resulting into intricate contact forces that must be maintained with a tight error bound. Given a large amount of degrees of freedom, intuitive control is an even more demanding task. This research addresses issues in the following areas: 1) domain
decomposition method to represent a complex object structure; 2) adaptive refinement and simplification of the model while preserving overall dynamic behavior; 3) robust constraint-based collision and contact analysis between deformable objects; and 4) constrained manipulation for intuitive and flexible user interface.
Constraint-based adaptive simulation method is currently applied to a virtual surgery system, and a functional anatomy visualization system. Finite element based deformable tissue model demonstrates a robust numerical result with a tight error bound at the contact area. Two new applications in cellular and molecular level simulation and visuaHzation are currently under investigation especially in the area of plasma membrane deformation and protein folding and docking. By having the constraint-based adaptive simulation system as an integrated and interactive tool for setting up initial conditions, simulation, and visualization, it can be used for an effective problem solving environment for many medical and bioinformatics applications.
Areas of Expertise: Bioengineering, Bioinformati.cs, Computer Graphics, Scientific Visualization
Current CU Collaborators: lmran Shah, Karl Reinig, Vic Spitzer
Needed Expertise: Bioengineering, Bioinformatics, Cellular Engineering Microsystems, Computational Biology, Medical Informatics, Proteomics, Tissue Engineering
Abstract Topic Keywords: Bioengineering, Bioinformatics, computational model, simulation, visualization
53
Author:
Appointment:
Campus:
School:
Department:
Campus Mail Address:
Campus Phone:
Campus Fax:
Email Address:
Web Site URL:
Submission Date:
Cios, Krzysztof (Krys) Full Professor Denver
Engineering and Applied Science Computer Science
Campus Box 1 09 (303) 556- 6314
() -
Krys.Cios@cudenver.edu
Sep 30, 2002 19:34~23
Title of Abstract: Complete Characterization of Posttranslatibnally MC?dified Proteins
Cios K ... , Duncan M.+, Askovic S.+, Gehrke A.*, Fung K.+ and Killcoyne S.+
CU Denver* and CU Health Sciences Center+
A sfngle gene often encodes for more than one protein and multiple forms of the same protein often exists in vivo. Differences in protein forms can be a result of an alternative start codon · and/or splicing, be due to chemical modification, or to varying degrees of degradation. Even a single amino acid substitution can have profound effects on protein tertiary structure, function and activity. As a result, it is of paramount importance to accurately determine the form of a protein that is present in vivo.
The challenge in proteomics therefore lies not in listing the proteins that are present in a biological sample, but in defining their precise form and function. Currently, relatively little attention is paid to this detail, and the algorithms that are extensively used in proteomic studies only employ a small subset of the available data in the interpretation process. Because these algorithms do not attempt to identify possible post-translational modifications, protein isoforms or variants, but only assigns a protein name, erroneous conclusions are frequently drawn.
We propose to construct a novel proteomics software package that includes the creation of a proteomics database that is dynamic and employs intelligent protein identification algorithms that accurately define the form of a protein. To achieve this objective the algorithms will utilize all the experimental data available to correctly identify a protein, including the assignment of post- translational modification and amino acid sequence variations. These objectives will be met by adopting a combination of several methods, including machine reaming, clustering and statistical analysis.
Areas of Expertise: data mining, machine learning, networks of spiking neurons, Proteomics
Current CU Collaborators: Accurso, Askovic, Duncan, Greenberg, Hunter, Jackson, Kafadar, Lezotte, Mannino, Newell, Osborne, Rewers, Shah, Zawada
Needed Expertise:
Abstract T oplc Keywords: Proteomics
55
Author:
Appointment:
Campus:
School:
Department:
Campus Mail Address:
Campus Phone:
Campus Fax:
Email Address:
Web Site URL:
Submission Date:
clarke, penny Assistant Professor Health Sciences Center Medicine
Neurology
Box 8182, UCHSC, 4200 East 9th (303) 393 - 4684
(303) 393 - 5271
Penny. Clarke@uchsc.edu
Oct 11, 2002 12:52:51
Title of Abstract: Reovirws-induced sensitization of human cancer cells to TRAIL
TNF-releated apoptosis inducing ligand {TRAIL) can induce apoptosis in a variety of human cancer cells and has potential for use in cancer treatment protocols. However, human cancer cells of all types differ in their sensitivity to TRAIL-induced apoptosis, limiting the applicability of this reagent.
Reoviruses are double-stranded RNA viruses that also induce apoptosis in human cancer cells (breast, lung, cervical, and ovarian) by a TRAIL-mediated mechanism. Reovirus-induced apoptosis is thus inhibited by soluble TRAIL receptors (Fc:DR4 and Fc:DR5), by anti-TRAIL antibiodies and by over-expression of the non-apoptosis inducing TRAIL receptor DcR-1.
Reovirus-induced apoptosis is also inhibited by other inhibitors of death receptor-mediated apoptosis, including dominant negative FADD and a peptide inhibitor of caspase 8. The central role that TRAIL plays in reovirus-induced apoptosis results in the fact that cells that are resistant to TRAIL are also resistant to reovirus-induced apoptosis, though not to reovirus-growth. We have shown that reovirus sensitizes human breast and lung cancer cells to killing by TRAIL. This requires caspase 8-activity and is associated with an increase in the activation of caspase 8 in cells treated with reovirus and TRAIL compared to cells treated with either of these agents alone.
We have also shown that reovirus activates the transcription factors NF-kB and c-Jun in infected cells. The activation of NF-kB is required for reovirus-induced apoptosis. The activaton of c-Jun is also associated with reovirus-induced apoptosis. Consequently, the ability of reassortant reoviruses to activate c-Jun correlates with their ability to induce apoptosis. In addition, the viral same gene segment that determines the ability of reoviruses to induce apoptosis also
determines the ability of reoviruses to activate c-Jun.
We hypothesize that reovirus-induced apoptosis and reovirus-induced sensitization of human cancer cells to TRAIL requires changes in gene expression in infected cells. Future studies will include an investigation of gene expression in TRAIL-treated or reovirus-infected cells and during reovirus-induced sensitization of cells to TRAIL. Dr. I an Maxwell, at UCHSC, is also interested in virus-induced changes in gene expression during parvovirus-induced killing of human melanoma cells. Dr. Maxwell is also applying to the symposium and we look forward to discussion about a potential collaboration. We feel that it would be extremely interesting to compare apoptotic mechanisms and alterations in gene expression that are triggered during virus-induced oncolysis in reovirus-and parvovirus-infected cells.
Areas of Expertise: Apoptosis, Cancer Biology, Molecular Biology, Signal Transduction, Virology
Current CU Collaborators: Gary Johnson, Lynn Heasley
Needed Expertise: Cancer Biology, Genomics, Proteomics, Signal Transduction
Abstract Topic Keywords: apoptosis, Cancer Biology, human cancer cells, reovirus, TRAIL
57
