The Role of the GATA2 Interactome in Erythropoiesis

项目摘要 我的目标是成为一名杰出的终身教职医生，科学家，专注于识别多样化的， 意想不到的细胞因子和途径，调节造血，并阐明了分子 其功能的机制。K 08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 作为一个成功的独立调查员。我的研究方向是转录因子 GATA 2，这是关键的出现的血液和骨髓的发展和维持过程中， 成人骨髓干细胞区室。在临床上，GATA 2的生殖系突变导致不良的 GATA 2缺乏综合征我假设有一个多样化的未被发现的网络， 与GATA 2相互作用以调节造血过程的蛋白质。为此，我开发了 与小鼠和人GATA 2反应的独特有效和特异性的抗GATA 2抗体， 这些鉴定了红系前体细胞中153种推定的GATA 2相互作用物。在这份提案中，我计划建立 这些蛋白质在GATA 2生物学以及人类和小鼠红细胞生成中的功能。我在这些支持 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，他们的努力如下： 我的主要导师Emery Bresnick博士是红细胞生物学、造血和加塔的国际专家 Igor Slukvin博士，诱导多能干细胞及其应用的国际专家， 张静博士，国际公认的恶性造血专家; Andreas Friedl，威斯康星大学麦迪逊分校病理学和实验室医学系主任， 我的职业发展和组织我的招聘。我还将享受来自葛颖博士的技术支持， 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学项目主任。 这些研究有可能从根本上扩展我们对少量转录是如何发生的理解。 这些因素完成了成功建立和维持健康骨骼所必需的各种功能 骨髓。研究结果将为独立研究和未来的R 01提案奠定基础。辅导 我在这项研究过程中获得的职业发展将使我成为一名出色的医生- 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.