Functional Components of the Rb/E2F and p53 Pathways

Rb/E2F 和 p53 通路的功能成分

基本信息

批准号：
8145250
负责人：
JEFFREY T CHANG
金额：
$ 22.98万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2013-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8145250
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 Process Promoter Regions Proteins Public Health RNA Interference Regulation Repression Research S Phase Series Small Interfering RNA Structure Structure-Activity Relationship Systems Biology Therapeutic Time Transcription Regulatory Protein Tumor Suppressor Proteins Variant Work anti-cancer therapeutic anticancer research base clinically significant drug sensitivity insight interest knock-down novel 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.

描述（由申请人提供）： RB/E2F肿瘤抑制途径的正常功能在所有人类肿瘤中均受到损害。因此，其功能和调节是癌症研究至关重要和强烈兴趣的领域。 PRB通过抑制E2F转录因子来控制细胞周期从G1-到S期的过渡。 RB/E2F途径调节了各种活动，并且对构成途径的功能成分进行了调查，将为癌症生物学提供宝贵的见解。为了更深入地了解RB/E2F途径，我建议将途径分解为使用计算方法的组成功能组件，然后研究途径成分的功能，调节机制和临床意义之间的关联。此外，我还将阐明相互交织的RB/E2F和p53途径之间的功能关系，从而对这些肿瘤抑制途径之间的复杂相互作用产生新的见解。为了调查这些问题，我将利用我先前开发的方法来分解途径并推断可推动其表达的转录调节蛋白。 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)和p53（凋亡）途径。这些研究将导致新方法的发展，这些方法提供了机会，以更深入地了解影响途径功能的确切成分，并在一般的细胞环境中阐明相互关联的途径之间的功能连接，这是系统生物学的目标。最终，表征和测量路径活动各个方面的能力将促进更精细调整的个性化治疗剂的发展。与公共卫生有关 RB是一种肿瘤抑制剂，在所有癌症中均功能失调，导致各种不良的级联 E2F蛋白带来的理解活动。我建议开发计算方法来识别这些活动并单独研究这些活动，而不是整体。我认为，这将导致对该途径的功能以及针对该途径的药物的更深入了解。