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Functional Components of the Rb/E2F and p53 Pathways

Rb/E2F 和 p53 通路的功能组件

基本信息

批准号：
7689222
负责人：
JEFFREY T CHANG
金额：
$ 9万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-30 至 2010-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7689222
关键词：
Algorithms Apoptosis Area Binding Sites Biological Process Cancer Biology Cell Cycle Cell Cycle Regulation Cell Line Collection Complex Computer Simulation Computing Methodologies DNA Damage Data Data Set Development Drug Delivery Systems E2F transcription factors Evolution Gene Expression Profile Genomics Goals Human In Vitro Individual Investigation Knowledge Lead Link Malignant Neoplasms Measures Mediating Methodology Methods Mitosis Molecular Pathway interactions Pattern Phase Principal Investigator Process Promoter Regions Proteins Public Health RNA Interference Regulation Repression Research Research Personnel Series Small Interfering RNA Structure Structure-Activity Relationship Systems Biology TP53 gene Therapeutic Time Transcription Regulatory Protein Tumor Suppressor Proteins Variant Work anti-cancer therapeutic anticancer research base clinical phenotype clinically significant drug sensitivity insight interest knock-down novel programs response transcription factor tumor

项目摘要

DESCRIPTION (provided by applicant): Normal function of the Rb/E2F tumor suppressor pathway is compromised in all human tumors. Therefore, its function and regulation are areas of critical importance and intense interest for cancer research. pRb controls the cell cycle transition from G1- to S-phase through its repression of the E2F transcription factors. The Rb/E2F pathway regulates a diverse set of activities, and an investigation into the functional components that comprise the pathway would provide valuable insight into the biology of cancer. To obtain a deeper understanding of the Rb/E2F pathway, I propose to decompose the pathway into its constituent functional components using a computational approach, and then to investigate the associations among the functions, regulatory mechanisms, and clinical significance of the pathway components. In addition, I will also elucidate the functional relationships between the intertwined Rb/E2F and p53 pathways, yielding novel insight into the complex interactions between these tumor suppressor pathways. To investigate these issues, I will leverage methods I previously developed to decompose pathways and to infer the transcriptional regulatory proteins that drive their expression. Thus, the goals of this proposal are: (1) to decompose the Rb/E2F pathway into a series of independently functional pathway components regulated by identifiable transcriptional regulatory proteins, (2) to evaluate the correspondence between the components of the Rb/E2F pathway and identified regulators of the cell cycle, and (3) to identify components that connect the intertwined Rb/E2F (cell cycle initiation) and p53 (apoptosis) pathways. These studies would lead to the development of novel methodologies that provide the opportunity to obtain a deeper understanding of the precise components that effect pathway functions, and elucidate the functional connections among the interrelated pathways in a general cellular context, a goal of systems biology. Ultimately, the ability to characterize and measure individual facets of pathway activity will facilitate the development of ever more finely tuned personalized therapeutics. RELEVANCE TO PUBLIC HEALTH Rb is a tumor suppressor that is dysfunctional in all cancers, leading to a cascade of various poorly understood activities brought about by the E2F proteins. I propose to develop computational methods to identify these activities and study them individually, instead of as a whole. I believe that this will lead to a deeper understanding of the function of this pathway, as well as the drugs that target it.