Epigenetic Regulation of Drosophila Germline Development

描述（申请人提供）：干细胞可以自我更新或分化为多种细胞类型。这些特性在再生医学中具有巨大的治疗潜力。了解调节干细胞身份和维持的分子机制将提供有关人类健康的基础知识，并可能加速干细胞在再生医学中的应用。表观遗传机制调节基因表达谱的动态变化，影响干细胞的自我更新和分化。我对研究Polycomb Group（PcG）介导的干细胞表观遗传调控特别感兴趣。我以前的工作特点是一种新的机制，调节PcG复合物，一个关键的表观遗传修饰剂，在从多能性到发育受限的细胞命运的过渡。目前，我正在研究PcG功能及其与Piwi在果蝇卵巢生殖系中的相互作用，这是易于遗传，基因组，分子以及细胞生物学分析。Piwi是生殖系干细胞的主要调节者。在指导阶段，我将描述Piwi-PcG相互作用，并确定这种相互作用如何影响果蝇卵巢生殖系和生殖系干细胞。在独立阶段，我将描述PcG功能的分子效应和Piwi-PcG相互作用在果蝇种系。这项研究将对干细胞生物学、表观遗传学以及再生医学产生重大影响。候选人：我的长期研究目标是研究表观遗传机制如何影响人类健康和疾病，特别是了解表观遗传机制如何调节复杂组织。我的长期职业目标是保持一个成功的独立研究计划，并教育未来的科学家。K99/R 00独立之路奖将使我获得实现长期研究和职业目标所需的关键培训。我将使用从这个提议中获得的实验数据作为我自己独立研究的基础。培训环境：我的顾问委员会和耶鲁大学为我提供了一个优秀的培训计划，一个激发智力的社区，以及一个支持良好的研究环境。在这个培训环境中，我将获得科学知识，研究专长，授权写作能力，实验室管理技能和其他领导技能。所有这些都将提高我获得终身教职的能力，实现我的长期研究和职业目标。 公共卫生相关性：干细胞的自我更新和可分化性在再生医学中具有巨大的治疗潜力。本研究以果蝇为模型系统，旨在了解调控基因表达的机制。这项工作将揭示有关干细胞生物学的基础知识，从而加速干细胞在再生医学中的应用。

DESCRIPTION (provided by applicant): Stem cells can self-renew or differentiate into multiple cell types. These properties promise great therapeutic potentials in regenerative medicine. Understanding the molecular mechanisms regulating stem cell identity and maintenance will provide fundamental knowledge about human health and likely accelerate the use of stem cells in regenerative medicine. Epigenetic mechanisms regulate dynamic changes of gene expression profiles to influence stem cell self-renewal and differentiation. I am especially interested in investigating Polycomb Group (PcG)-mediated epigenetic regulation of stem cells. My previous work characterized a novel mechanism regulating a PcG complex, a key epigenetic modifier, during the transition from pluripotency to developmentally restricted cell fates. Currently, I am investigating PcG functions and their interaction with Piwi in Drosophila ovarian germline, which is tractable to genetic, genomic, molecular, as well as cell biological analyses. Piwi is a master regulator of germline stem cells. During the mentored phase, I will characterize Piwi-PcG interaction and determine how this interaction impacts Drosophila ovarian germline and germline stem cells. During the independent phase, I will characterize the molecular effects of PcG functions and Piwi-PcG interaction in Drosophila germline. This study will have significant impact on stem cell biology, epigenetics, as well as regenerative medicine. Candidate: My long-term research goal is to investigate how epigenetic mechanisms impact human health and disease, specifically to understand how epigenetic mechanisms regulate complex tissues. My long-term career goals are to maintain a successful independent research program and educate future scientists. The K99/R00 Pathway to Independence Award will allow me to gain the critical training needed to achieve my long-term research and career goals. I will use experimental data obtained from this proposal as the basis for my own independent research. Training environment: Dr. Haifan Lin (mentor), my advisory committee, and Yale University provide an excellent training program, an intellectually stimulating community, and a well-supported research environment. In this training environment I will gain scientific knowledge, research expertise, grant writing ability, lab management skill, and additional leadership skills. All these will enhance my ability to obtain a tenure-track faculty position and achieve my long-term research and career goals. PUBLIC HEALTH RELEVANCE: The self-renewal and differentiability of stem cells promise great therapeutic potentials in regenerative medicine. This proposal aims to understand the mechanisms regulating gene expression that program stem cell identity by using Drosophila as the model system. This work would reveal fundamental knowledge about stem cell biology, thereby accelerating the use of stem cells in regenerative medicine.