Functional Components of the Rb/E2F and p53 Pathways

描述(由申请人提供)： Rb/E2F抑癌通路的正常功能在所有人类肿瘤中都是受损的。因此，它的功能和调控是癌症研究中至关重要和强烈兴趣的领域。PRb通过抑制E2F转录因子调控细胞周期从G1期向S期的转变。Rb/E2F途径调节一系列不同的活动，对组成该途径的功能成分的研究将为癌症生物学提供有价值的见解。 为了更深入地了解RB/E2F途径，我建议将该途径分解为 使用计算方法，然后调查这些通路组件的功能、调节机制和临床意义之间的关联。此外，我还将阐明交织在一起的Rb/E2F和P53通路之间的功能关系，从而对这些肿瘤抑制通路之间的复杂相互作用产生新的见解。为了研究这些问题，我将利用我之前开发的方法来分解途径，并推断驱动它们表达的转录调控蛋白。因此，这个建议的目标是：(1)将Rb/E2F途径分解成一系列由可识别的转录调节蛋白调控的独立功能的途径成分，(2)评估Rb/E2F途径成分与已识别的细胞周期调控因子之间的对应关系，以及(3)识别连接相互交织的Rb/E2F(细胞周期起始)和P53(细胞凋亡)途径的成分。 这些研究将导致新方法的发展，从而有机会更深入地了解影响通路功能的精确成分，并在一般细胞背景下阐明相互关联的通路之间的功能联系，这是系统生物学的目标。最终，表征和测量通路活动的各个方面的能力将促进更精细调整的个性化治疗的发展。 与公共卫生的相关性 Rb是一种肿瘤抑制因子，在所有癌症中都是功能失调的，导致各种不良反应的级联。 了解E2F蛋白带来的活动。我建议开发计算方法来识别这些活动，并对它们进行单独研究，而不是作为一个整体。我相信，这将使人们更深入地了解这一途径的功能，以及针对它的药物。

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.