Integration of HSC Stress Responses and Disease Progression by DNMT3A Mutations

摘要 在这篇独立之路奖的申请中，克莉丝汀（若超）张博士详细介绍了她的职业生涯。 发展计划，以战略性地增强她在血液学趋势方面的知识和她在国家- 最先进的技术，同时询问Dnmt 3a突变如何赋予造血干细胞（HSC）适应性 在慢性炎症和疾病进展的主要缺陷造血过程中的优势。 博士Zhang是华盛顿大学医学院的博士后研究助理， 表观遗传学和遗传学背景，具有各种技术技能。在此，她想了解 表观遗传扰动如何导致造血缺陷并因此导致血液疾病。主 张博士的目标是成为表观遗传血液学的独立研究者。张博士提议 职业发展计划，在那里，她将与非常成功的，世界知名的领导人进行严格的培训 在血液学，包括造血干细胞和祖细胞（HSPC）生物学（格兰特挑战博士），骨 骨髓生态位和病理学（丹尼尔林克博士），和疾病造血（蒂莫西利博士）。她出色 导师团队将确保她成功实现这一雄心勃勃的目标。张博士会变得更强壮 HSPC生物学、骨髓成分和血液病病理学知识; 2） 单细胞水平和多重成像分析的高级表观遗传分析; 3）关键的软技能 这是一个成功和创新的独立实验室。 在衰老过程中，在HSC隔室中获得的DNA甲基转移酶3A（DNMT 3A）的体细胞突变导致 克隆性造血（CH），一种与血液病风险增加相关的疾病。的 DNMT 3A-CH（10%）和血液病（~1%）之间的患病率不成比例，表明环境 对于疾病进展的克隆选择和进化可能需要压力。虽然累积 有证据表明DNMT 3A突变可以通过慢性干扰素-γ（IFNg）信号传导来选择， 在慢性炎症期间，DNMT 3A突变如何赋予HSC适应性优势仍然是难以捉摸的; Dnmt 3a突变型HSC的扩增重塑了骨髓组成， 条件本研究的目的是探讨HSC适应性优势的机制 通过Dnmt 3a突变传达，并了解慢性选择性造血缺陷是如何发生的。 炎症引起至少部分归因于骨髓重塑的疾病状况。 该提案的总体目标是将张博士培养成为一名成功的独立研究者， 表观遗传血液学从拟议的研究和职业生涯中获得的知识和经验 她的发展计划将坚定地使她成为表观遗传血液学的主要研究者。

ABSTRACT In this Pathway to Independence Award application, Dr. Christine (Ruochao) Zhang outlines detailed career developmental plans to strategically enhance her knowledge in trending hematology and her expertise of state- of-the-art techniques while interrogating how Dnmt3a mutations endow hematopoietic stem cells (HSC) a fitness advantage during chronic inflammation and prime defective hematopoiesis for disease progression. Dr. Zhang is a postdoctoral research associate at the Washington University School of Medicine and has a strong background in epigenetics and genetics with a diverse range of technical skills. Herein, she wants to understand how epigenetic perturbations lead to defective hematopoiesis and consequently blood diseases. The primary goal of Dr. Zhang is to become an independent investigator in epigenetic hematology. Dr. Zhang has proposed career development plans, where she will be rigorously trained with highly successful, world-renowned leaders in hematology, including hematopoietic stem and progenitor cell (HSPC) biology (Dr. Grant Challen), bone marrow niche and pathology (Dr. Daniel Link), and disease hematopoiesis (Dr. Timothy Ley). Her outstanding mentor team will ensure her success in reaching this ambitious goal. Dr. Zhang will gain 1) strengthened knowledge in HSPC biology, bone marrow composition, and hematologic disease pathology; 2) expertise in advanced epigenetic analysis at the single-cell level and in multiplex imaging analysis; 3) critical soft skills required for running a successful and innovative independent laboratory. Somatic mutations in DNA methyltransferase 3A (DNMT3A) acquired in the HSC compartment during aging give rise to clonal hematopoiesis (CH), a condition associated with increased risks of hematologic diseases. The disproportional prevalence between DNMT3A-CH (10%) and blood diseases (~1%) suggests environmental pressures are likely required for clonal selection and evolution for disease progression. While cumulative evidence has suggested that DNMT3A mutations can be selected by chronic interferon-gamma (IFNg) signaling, it remains elusive how DNMT3A mutations confer a fitness advantage to HSCs during chronic inflammation; how the expansion of Dnmt3a-mutant HSCs reshapes the bone marrow composition and ultimately leading to disease conditions. The goal of this study is to interrogate the mechanism(s) underlying the HSC fitness advantage conveyed by Dnmt3a mutations and to understand how the defective hematopoiesis selected by chronic inflammation gives rise to disease conditions at least in part attributed to bone marrow remodeling. The overarching goal of this proposal is to develop Dr. Zhang into a successful independent investigator in epigenetic hematology. The knowledge and experience acquired from the proposed studies and the career development plan will firmly set her on the path to becoming a leading investigator of epigenetic hematology.