Defining the human telomere signaling networks and their implication in cancer

描述（由申请人提供）：端粒功能障碍是癌症等疾病的一个有据可查的促成因素。我们提出的工作应该确定新的目标和途径，并提供其功能的机制细节，从而促进我们确定新的治疗靶点，获得对疾病启动的途径和信号的新见解，并阐明新的和更有效的治疗方案。我们推测，不同的和未表征的类信号和调节蛋白直接结合到核心端粒蛋白和调节端粒稳态。我们的长期目标是阐明端粒蛋白及其相关因子调节端粒上各种信号通路的机制。该项目的目标是系统地识别由端粒蛋白如TRF2招募到端粒的新型调节剂，并研究这些靶点如何参与端粒调节。该提案的具体目标是：具体目标1：系统地识别新的端粒调节器和信号网络。将采用全基因组方法来识别TRF2的新细胞靶点，并生成以TRF2为中心的信号网络的高分辨率图谱。建议进行二级筛选，以确认所确定的目标并确定其优先次序。具体目标2：确定新确定的监管机构的职能。这个目标将集中在新的TRF2目标PNUTS和泛素E3连接酶，在他们的TRF2功能和端粒的维护，以及可能的作用，在额外的端粒活动的调节。

DESCRIPTION (provided by applicant): Telomere dysfunction is a well-documented contributing factor to diseases such as cancer. Our proposed work should identify new targets and pathways and provide mechanistic details of their function, thereby facilitating in our identifying novel targets for therapies, gaining new insight into the pathways and signals for disease initiation, and shedding light on new and more effective treatment options. We hypothesize that distinct and uncharacterized classes of signaling and regulatory proteins bind directly to core telomeric proteins and modulate telomere homeostasis. Our long-term goal is to elucidate the mechanisms by which telomeric proteins and their associated factors regulate various signaling pathways at the telomeres. The goal of this project is to systematically identify novel regulators recruited to the telomeres by telomeric proteins such as TRF2, and to study how these targets may participate in telomere regulation. The specific aims of the proposal are: Specific Aim 1: To systematically identify new telomere regulators and signaling networks. Genome-wide approaches will be employed to identify new cellular targets of TRF2, and generate high-resolution maps of TRF2-centric signaling networks. Secondary screens are proposed to confirm and prioritize the targets identified. Specific Aim 2: To determine the function of the newly identified regulators. This aim will focus on new TRF2 targets PNUTS and ubiquitin E3 ligases, in their regulation of TRF2 function and telomere maintenance, and possible roles in extra-telomeric activities.