The Role of the GATA2 Interactome in Erythropoiesis

GATA2 相互作用组在红细胞生成中的作用

• 批准号: 10625977
• 负责人: Daniel R. Matson
• 金额: $ 15.69万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625977
• 关键词: Acetyltransferase; Adult; Advisory Committees; Age; Alveolar; Antibodies; Applied Research; Automobile Driving; Base Sequence; Basic Science; Binding; Biology; Blood; Bone Diseases; Bone Marrow; Bone Marrow Stem Cell; Bone marrow failure; CD34 gene; Cell Compartmentation; Cell Line; Cells; Cellular biology; Chromatin; Clinical; Communities; Complex; Coupled; Data; Development; Disease; Enhancers; Erythroblasts; Erythrocytes; Erythroid; Erythroid Progenitor Cells; Erythropoiesis; Family; Fetal Liver; Foundations; Future; GATA1 gene; Generations; Genes; Genetic Transcription; Genome; Germ-Line Mutation; Goals; Hematological Disease; Hematology; Hematopoiesis; Hematopoietic System; Hematopoietic stem cells; Homeostasis; Human; Immunologic Deficiency Syndromes; Immunoprecipitation; International; K-Series Research Career Programs; Laboratories; Lead; Link; Lower Extremity; Lymphatic; Lymphedema; Maintenance; Malignant - descriptor; Marrow; Mass Spectrum Analysis; Measures; Medicine; Mentors; Molecular; Mus; Mutation; Output; Pathology; Pathway interactions; Patients; Penetrance; Phenocopy; Physicians; Physiological; Process; Proliferating; Proteins; Proteomics; Public Health; Reaction; Regulatory Element; Repression; Research; Research Personnel; Role; Scientist; Sensorineural Hearing Loss; Site; Specificity; Structure; Symptoms; Syndrome; Testing; Time; Training Programs; Validation; Variant; Zinc Fingers; career development; chromatin immunoprecipitation; cohort; disease-causing mutation; enhancer-binding protein AP-4; erythroid differentiation; experience; experimental study; histone acetyltransferase; induced pluripotent stem cell; member; mutant; patient variability; professor; progenitor; progenitor system; programs; protein function; recruit; regenerative biology; tenure track; transcription factor

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.

项目概要 我的目标是成为一名杰出的终身医师科学家，专注于识别多样化和 调节造血作用的意想不到的细胞因子和途径，并阐明分子机制 其作用机制。该 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，以完成严格且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。我提议的研究重点是转录因子 GATA2，在发育和维持过程中对于血液和骨髓的出现至关重要 成人的骨髓干细胞室。临床上，GATA2 种系突变会导致不良反应 了解 GATA2 缺乏综合症。我假设存在一个多样化且未被发现的网络 与 GATA2 相互作用以调节造血过程的蛋白质。为此，我开发了 独特有效且特异性的抗 GATA2 抗体，可与小鼠和人类 GATA2 发生反应并利用 这些用于鉴定红系前体细胞中 153 个假定的 GATA2 相互作用因子。在这个提案中，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。我在这些方面得到支持 由组成我的研究咨询委员会的优秀研究人员和导师组成的团队的努力： 我的主要导师 Emery Bresnick 博士，红细胞生物学、造血和 GATA 领域的国际专家 因素； Igor Slukvin博士，国际诱导多能干细胞及其基础应用专家 和应用科学；张静博士，国际公认的恶性造血专家；和博士。 Andreas Friedl，威斯康星大学麦迪逊分校病理学和实验医学系主任，曾指导 我的职业发展并组织了我的招聘。我还将享受到葛莺博士的技术支持， 威斯康星大学麦迪逊分校细胞和再生生物学教授兼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如何进行的理解。 因素完成成功建立和维持健康骨骼所需的多种功能 骨髓。结果将构成独立研究和未来 R01 提案的基础。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做好准备- 科学家并将我融入更大的血液学界。