BIOMEDICAL INFORMATICS RESEARCH

1. T T T T T BIOMEDICAL INFORMATICS RESEARCH P R O G R A M O V E R V I E W High Throughput Molecular Fingerprinting of Cancer The purpose of this study is to accurately classify the molecular profiles obtained from blood, urine, and tissue biopsy according to known clinical outcomes. Advanced bioninformatics techniques will be used for pattern recognition and clustering of molecular profiles based on an integrated dataset with known clinical outcomes. The aim is to augment presently available diagnostic and staging methodology with easy-to-use molecular profiling for early detection and accurate classification of sub-stages of breast and prostate cancers. Informatics Center for Mouse Neurogenetics The purpose of this Neuroinformatics project is to develop and exploit a suite of image databases, motorized Internet microscopes, and software to study the genetic basis of structural variation of the mouse CNS. Resources are open to the research community through an integrated web interface at <nervenet.org>. The focus of this project is to provide a collaborative research environment for mapping quantitative trait loci (QTLs). These genes are responsible for the extraordinary variation in CNS structure among mice and humans. QTL analysis is a burgeoning field that tackles complex biological traits modulated by many genes. Ultra-High Speed Optical Network Architecture We are making use of high-speed fiber-optic networking technology to develop a distributed genomic and anatomical database. The system will combine databases and software developed at the Center for Bioinformatics at the University of Pennsylvania (PCBI) – including databases of genetic and physical maps, genomic sequence, transcribed sequences and gene expression data all linked to external biology databases and internal project data – with brain atlas data and visualization packages developed at the Computer Vision Laboratory for Vertebrate Brain Mapping (CVCVBM) at MCP Hahnemann University. The value of the project lies in the ability to correlate specific brain structures with molecular and physiological process. GABA A receptors in aging and Alzheimers Disease Gamma-amino butyric acid (GABA), the major inhibitory neurotransmitter in the mammalian CNS, hyperpolarizes neuronal membranes by opening a C1 channel intrinsic to the GABA A receptor. The proposed studies investigate the anatomical features and expression of selected GABA A receptor subunits (i.e., alpha1, alpha2, alpha3, alpha4, alpha5, beta1-3, gama2) in human hippocampus of non-pathologic mature and aged individuals (30-90 years of age) and those with Alzheimer's disease (AD) pathology. • Faculty/Contact:Aydin Tozeren, Ph.D. • E-mail: tozeren@coe.drexel.edu

2. The findings from this study will be useful for early detection of cancer and for effectively monitoring the impact of life style changes (eating habits, exercise, support system) on the onset and/or progression of cancer by monitoring the patterns of multiple markers in blood serum and other fluids. Accurate classification of cancer will eliminate the need for excessive use of chemical and hormonal therapy, and will lead to rational cancer-subtype specific drug design based on the molecular profiles associated with each subtype. This methodology will translate to better health and lower cost of managed care. Protein expression mapping for breast cancer Protein networks determine cancer outcome HIGH THROUGHPUT MOLECULAR FINGERPRINTING OF CANCER P R O G R A M O V E R V I E W The main theme of the proposed study is to use the patterns of expression of a cluster of markers rather than the presence of cancer surrogate markers in a solid or fluid tissue for diagnosis and treatment of cancer. Research outcomes are (a) mathematical determination of molecular patterns obtained from blood serum (or urine) using diagnostic tools and (b) integration and definition of molecular patterns obtained by analysis of solid and fluid tissue and (c) development of new methods for accurate sub-classification (staging) of cancer and individualized treatment. Early detection of breast and prostate cancer is essential for saving lives, maintaining quality of life, and reducing healthcare costs. Unfortunately, there is still no early marker for breast cancer, and the prostate specific antigen (PSA) test for prostate cancer is not sensitive enough. For example, it is estimated that 10 million males in the US have latent prostate cancer, but only 132,000 are diagnosed each year using the available techniques. The proposed study focuses on the likelihood that patterns of presence (amounts) and absence of multiple numbers of surrogate protein markers in biofluids (blood serum, breast aspiration fluid, or urine) can be an effective tool in early detection of breast and prostate cancer. Secondly, mathematical patterns of molecular profiles obtained from solid tissue and profiles from biofluids will be used for accurate classification and staging of breast and prostate cancer. Accurate staging of cancer is extremely important because recent studies indicate that a significant percentage of Stage II breast cancer patients receive unnecessary chemotherapy with toxic side effects due to a lack of accurate subdivisions of cancer stages. In the other extreme, patients in the better "prognosis" category manifest aggressive disease. The proposed study will therefore facilitate the discovery of early markers for cancer and will lead to individualized treatments, thereby saving lives and increasing the quality of life. • Faculty/Contact:Aydin Tozeren, Ph.D. • E-mail: tozeren@coe.drexel.edu • Collaborating Researchers: P. Lelkes, Ph.D., A. Shokoufandeh, Ph.D. and I. Y.Song, PhD. (Drexel University); M. Stearns, Ph.D. (MCP Hahnemann). • Funding: Pennsylvania Department of Health; SEPTA Greenhouse Grant. • Laboratories: Drexel Histology Laboratory; Genomics and Proteomics Lab at the Winber Research Institute

3. T T T Jonathan Nissanov, Ph.D., is a neurobiologist and biomedical engineer who has worked for many years on the problem of spatial normalization of rodent brain maps. T T INFORMATICS CENTER FOR MOUSE NEUROGENETICS P R O J E C T O N E P A G E R • The purpose of this Neuroinformatics project is to develop and exploit a suite of image databases, motorized Internet microscopes, and software to study the genetic basis of structural variation of the mouse CNS. Resources are open to the research community through an integrated web interface at <nervenet.org>. The focus of this project is to provide a collaborative research environment for mapping quantitative trait loci (QTLs). These genes are responsible for the extraordinary variation in CNS structure among mice and humans. QTL analysis is a burgeoning field that tackles complex biological traits modulated by many genes. We will develop four significant new resources and technologies: The Mouse Brain Library (MBL) consists of a huge, well-organized library of brain sections suitable for morphometric investigation. Thousands of images can be rapidly searched, sorted, and downloaded at a resolution of five microns per pixel using an intuitive and powerful web interface. The Internet Microscope System (iScope) captures and displays extremely detailed movies – Z-axis image stacks – suitable for sophisticated stereological study of all brains in the MBL. The iScope includes robotic slide handlers controlled via the Web 24 hours a day, 7 days a week. The NeuroCartographer Project will develop a suite of software tools and 3D models of hundreds of neuroanatomical structures, enabling researchers to reconstruct and digitally dissect MBL material. The Neurogenetics Tool Box (NTB) comprises a set of gene mapping programs that will enable neuroscientists to rapidly identify and evaluate QTLs responsible for the astonishing variation in CNS architecture. The NTB will include genotypes from an unusually large advanced intercross designed to map loci with sufficient precision, thus enabling a candidate gene approach to cloning QTLs. Achieving the aims of these four projects will catalyze a new era in the structural analysis of the adult mammalian nervous system and will lead to a large number of novel lines of research regarding the development, aging, and pathology of the human brain. • Faculty/Contact:Jonathan Nissanov, Ph.D. • E-mail: nissanov@drexel.edu • Collaborating Researchers:O. Tretiak, PhD., Drexel University; D. Goldowitz, PhD., U. of Tennessee; R. Williams, PhD., U. of Tennessee; K. Manly, PhD., Rosewell Park Cancer Institute; G. Rosen, PhD., Harvard University. • Funding: NIMH, The Human Brain Project. • Laboratories:Computer Vision  Laboratory for Vertebrate Brain Mapping.

4. We are making use of high-speed fiber-optic networking technology to develop a distributed genomic and anatomical database. The system will combine databases and software developed at the Center for Bioinformatics at the University of Pennsylvania (PCBI) – including databases of genetic and physical maps, genomic sequence, transcribed sequences and gene expression data all linked to external biology databases and internal project data – with brain atlas data and visualization packages developed at the Computer Vision Laboratory for Vertebrate Brain Mapping (CVCVBM) at MCP Hahnemann University. The value of the project lies in the ability to correlate specific brain structures with molecular and physiological process. ULTRA-HIGH SPEED OPTICAL NETWORK ARCHITECTURE P R O G R A M O V E R V I E W This project has four principal objectives: (1) Explore new methods and protocols for managing differentiated, prioritized quality-of-service; efficient resource allocation and re-allocation; and ensuring network integrity in next generation Internets. (2) Create and demonstrate a very high capacity (5 Tbps) router based on a passive optical switching core surrounded by port and buffer modules. (3) Create and demonstrate all-optical networking components, including an all optical regenerator. (4) Demonstrate high-speed (1 Gbps) networking applications. Our laboratory is involved in the fourth of these objectives. • Faculty/Contact:Jonathan Nissanov, Ph.D. • E-mail: nissanov@drexel.edu • Collaborating Researchers:S. Personick, PhD., Drexel University; S. Davidson, PhD., U. of Pennsylvania; C. Stoeckert, PhD., U. of Pennsylvania. • Funding: Defense Advanced Research Projects Agency (DARPA), Next Generation Internet Initiative. • Laboratories:Computer Vision  Laboratory for Vertebrate Brain Mapping.

5. Moreover, brain tissue obtained from elderly patients will not only show altered levels of expression of specific GABA A subunits, but will have a different subunit composition of the GABA A receptor complex compared to the controls. In AD, we hypo- thesize that these receptor subunits will also display altered levels of expression and binding within selected sub-regions of the hippocampus. In addition, many of these changes will occur during the early phases of the disease (i.e., plastic/ compensatory phase) and will be unique from those observed during the end stages of the disease (i.e., neuro-degenerative phase). A unique aspect of this research is the study of both aging and AD subjects. Notably, a comparison of these two populations of subjects will provide us with the opportunity of differentiating whether alterations in the anatomy of specific GABA A receptor subunits are associated with normal aging or represent a neuropathologic process. GABA A RECEPTORS IN AGING AND ALZHEIMERS DISEASE P R O G R A M O V E R V I E W Gamma-amino butyric acid (GABA), the major inhibitory neurotransmitter in the mammalian CNS, hyperpolarizes neuronal membranes by opening a C1 channel intrinsic to the GABA A receptor. The proposed studies investigate the anatomical features and expression of selected GABA A receptor subunits (i.e., alpha1, alpha2, alpha3, alpha4, alpha5, beta1-3, gama2) in human hippocampus of non-pathologic mature and aged individuals (30-90 years of age) and those with Alzheimer's disease (AD) pathology. Underlying these studies are investigations of the PI and co-investigators demonstrating (i) subunit specific alteration (i.e., alpha1) in the CA1 field and dentate gyrus of aged rats; (ii) GABA A receptor subunit protein and mRNA alterations (i.e., alpha1, beta2, beta3) in the hippocampal formation of aged brains with AD pathology; (iii) time-dependent alterations of GABA A beta2/3 immunoreactivity in the dentate gyrus following perforant pathway lesions. In addition, pharmacological studies have demonstrated altered drug sensitivities, for example, to benzodiazepines in the elderly. To date, it is not known the extent to which altered drug responses in the elderly may be attributed to emotional or physical disease, a surplus or lack of nutrition, use or abuse of other medications, or alterations in the molecular composition of the GABA A receptor. Throughout these studies we will employ immunohistochemical, in situ hybridization, in situ autoradiogaphic, and biochemical techniques to study the regional and laminar pattern of GABA A receptor subunit protein and mRNA expression in the hippocampal formation of aging individuals (SPECIFIC AIM 1), as well as those with a varying extent of AD pathology (SPECIFIC AIM 2). It is our hypothesis that selected GABA A receptor subunits will display differential levels of expression and binding within the various regions of the hippocampus. • Faculty/Contact:Jonathan Nissanov, Ph.D. • E-mail: nissanov@drexel.edu • Collaborating Researchers:D. Armstrong, PhD., Lankenau Medical research Center. • Funding: National Institute on Aging (NIA). • Laboratories:Computer Vision  Laboratory for Vertebrate Brain Mapping.