The Role of the GATA2 Interactome in Erythropoiesis

项目总结 我的目标是成为一名杰出的终身教职医生兼科学家，专注于识别不同的和 调控造血的意想不到的细胞因子和途径，并阐明分子 它们的作用机制。这项K08指导临床科学家研究职业发展奖将 为我提供必要的支持，以完成严格和结构化的培训计划，并建立 我自己是一名成功的独立调查员。我建议的研究重点是转录因子 GATA2，在发育和维持过程中对血液和骨髓的出现是至关重要的 成人的骨髓干细胞室。临床上，GATA2的生殖系突变会导致不良的 了解GATA2缺乏症。我假设有一个多样化的和未被发现的网络 与GATA2相互作用以调节造血过程的蛋白质。为此，我开发了 独特有效和特异的抗GATA2抗体，可与小鼠和人GATA2反应，并利用 以确定红系前体细胞中153个可能的GATA2相互作用因子。在这项提案中，我计划建立 这些蛋白质如何在GATA2生物学以及人类和小鼠红细胞生成中发挥作用。我在这些方面得到了支持 我的研究咨询委员会由一群有成就的研究人员和导师组成的团队所做的努力： 我的主要导师埃默里·布雷斯尼克博士是一位红细胞生物学、造血和GATA方面的国际专家 因素；国际诱导多能干细胞专家伊戈尔·斯卢克文博士及其在基础研究中的应用 国际公认的恶性血液病专家张静博士和张静博士。 安德烈亚斯·弗里德尔，威斯康星大学麦迪逊分校病理和实验室医学部主任，他曾指导 我的职业发展和组织我的招聘。我还将享受英格博士的技术支持， 细胞和再生生物学教授，威斯康星大学麦迪逊分校人类蛋白质组计划主任。 这些研究有可能从根本上扩大我们对少量转录如何 这些因素完成了成功建立和维护健康骨骼所需的各种功能 骨髓。研究结果将成为独立研究和未来R01提案的基础。指导工作 我在研究过程中得到的职业发展将为我成为一名出色的医生做好准备- 科学家，让我融入更大的血液学社区。

PROJECT SUMMARY My goal is to become an exceptional tenure track physician-scientist focused on identifying diverse and unexpected cellular factors and pathways that regulate hematopoiesis, and elucidating the molecular mechanisms of their function. This K08 Mentored Clinical Scientist Research Career Development Award would provide me with the necessary support to complete a rigorous and structured training program and establish myself as a successful independent investigator. My proposed research focuses on the transcription factor GATA2, which is critical for emergence of the blood and bone marrow during development and maintenance of the bone marrow stem cell compartment in adults. Clinically, germline mutations in GATA2 cause the poorly understood GATA2 Deficiency Syndrome. I hypothesize that there is a diverse and undiscovered network of proteins that interface with GATA2 to modulate the process of hematopoiesis. To this end, I have developed uniquely effective and specific anti-GATA2 antibodies that react with mouse and human GATA2 and utilized these to identify 153 putative GATA2 interactors in erythroid precursor cells. In this proposal, I plan to establish how these proteins function in GATA2 biology and in human and mouse erythropoiesis. I am supported in these efforts by a team of accomplished investigators and mentors who constitute my Research Advisory Committee: my primary mentor Dr. Emery Bresnick, an international expert in red cell biology, hematopoiesis and GATA factors; Dr. Igor Slukvin, an international expert on induced pluripotent stem cells and their application for basic and applied science; Dr. Jing Zhang, an internationally recognized expert on malignant hematopoiesis; and Dr. Andreas Friedl, Chair of the UW-Madison Department of Pathology and Laboratory Medicine who has guided my career development and organized my recruitment. I will also enjoy technical support from Dr. Ying Ge, Professor of Cell and Regenerative Biology and Director of the Human Proteomics Program at UW-Madison. These studies have the potential to radically expand our understanding of how a small number of transcription factors accomplish the wide variety of functions necessary to successfully establish and maintain a healthy bone marrow. The results will form the foundation for independent studies and future R01 proposals. The mentoring and career development that I receive during the course of this research will prepare me to excel as a physician- scientist and integrate me into the greater hematology community.