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充分证据的促进因素。我们提议的工作应该确定新的靶点和途径，并提供其功能的机械细节，从而有助于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，并为新的和更有效的治疗方案提供线索。我们假设，不同的和未表征的信号和调节蛋白直接与核心端粒蛋白结合，并调节端粒的稳态。我们的长期目标是阐明端粒蛋白及其相关因子调节端粒不同信号通路的机制。该项目的目标是系统地识别端粒蛋白如TRF2招募到端粒的新的调节因子，并研究这些靶标如何参与端粒调节。该提案的具体目标是：具体目标1：系统地确定新的端粒调节因子和信号网络。全基因组的方法将被用来识别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地图。建议进行二次筛选，以确认已确定的目标并确定其优先顺序。具体目标2：确定新确定的监管机构的职能。这一目标将集中于新的TRF2靶标PNUTS和泛素E3连接酶，它们在TRF2功能和端粒维持中的调节，以及在端粒外活动中的可能作用。

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.