Integration of HSC Stress Responses and Disease Progression by DNMT3A Mutations

DNMT3A 突变整合 HSC 应激反应和疾病进展

• 批准号: 10693337
• 负责人: Christine R Zhang
• 金额: $ 8.81万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10693337
• 关键词: Accounting; Address; Age; Aging; Anemia; Aplastic Anemia; Architecture; Autoimmune; Award; Blood; Blood Platelets; Bone Marrow; Bone Marrow Cells; Bone remodeling; Cell Compartmentation; Cells; Cellular biology; Chromatin; Chronic; Clinical; Clonal Expansion; Clonal Hematopoietic Stem Cell; DNA Modification Methylases; DNMT3a; DNMT3a mutation; Data; Development; Development Plans; Disease; Disease Progression; Dysmyelopoietic Syndromes; Early Intervention; Elderly; Endowment; Ensure; Epigenetic Process; Erythrocytes; Erythroid; Erythroid Progenitor Cells; Evolution; Exposure to; Genes; Genetic; Goals; Grant; Hematological Disease; Hematology; Hematopoiesis; Hematopoietic stem cells; Imaging Device; Indolent; Infection; Inflammation; Interferon Type II; Knowledge; Laboratories; Lead; Lesion; Link; Megakaryocytes; Mentors; Modeling; Molecular; Multipotent Stem Cells; Mus; Mutant Strains Mice; Mutate; Mutation; Obesity; Outcome Study; Pathology; Pathway interactions; Persons; Phenotype; Population; Postdoctoral Fellow; Prevalence; Property; Recurrence; Research Personnel; Risk; Risk Reduction; Running; Serum; Shapes; Signal Transduction; Somatic Mutation; Stress; Symptoms; T-Lymphocyte; TP53 gene; Technical Expertise; Techniques; Testing; Therapeutic; Training; Transplantation; Universities; Up-Regulation; Variant; Washington; age related; aging population; biochemical tools; biological adaptation to stress; cardiovascular disorder risk; career; career development; disease phenotype; experience; fitness; genetic manipulation; hematopoietic stem cell quiescence; improved; inflammatory milieu; innovation; medical schools; microbial; multiple omics; multiplexed imaging; mutant; mutant mouse model; overexpression; pressure; reconstitution; response; skills; stem cells; success; transcriptome; trend

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.

摘要 在这篇独立之路奖的申请中，张若超博士勾勒出了详细的职业生涯 发展计划，以战略性地增强她在趋势血液学方面的知识和她在状态- 最先进的技术，同时询问DNMT3A突变如何赋予造血干细胞(HSC)适合性 在慢性炎症期间的优势和在疾病进展中最初的造血缺陷。 张博士是华盛顿大学医学院的博士后研究助理，拥有强大的 具有表观遗传学和遗传学背景，具有多种技术技能。在这里，她想要了解 表观遗传扰动如何导致有缺陷的造血，从而导致血液疾病。初级阶段 张博士的目标是成为表观遗传血液学的独立研究员。张博士提出了 职业发展计划，在那里她将接受非常成功的世界知名领导人的严格培训 血液学，包括造血干细胞和祖细胞(HSPC)生物学(Grant Challen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·莱伊博士)。她的杰出之处 导师团队将确保她成功实现这一雄心勃勃的目标。张博士将获得更强大的力量 具有HSPC生物学、骨髓成分和血液病病理学方面的知识；2)具备 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 运营一个成功和创新的独立实验室所必需的。 衰老过程中HSC间获得的DNA甲基转移酶3A(DNMT3A)的体细胞突变 上升为克隆性造血(CH)，这是一种与血液病风险增加相关的疾病。这个 DNMT3A-CH(10%)和血液疾病(~1%)的不成比例患病率表明环境因素 克隆选择和疾病进展的进化可能需要压力。而累积 有证据表明，DNMT3A突变可以通过慢性干扰素-γ(IFNG)信号来选择， 在慢性炎症期间，DNMT3A突变如何赋予HSCs健康优势仍不清楚；如何 DNMT3A突变的造血干细胞的扩增会重塑骨髓成分，并最终导致疾病 条件。本研究的目的是探讨高血压病患者体能优势背后的机制(S 通过DNMT3A突变和了解慢性造血缺陷是如何选择的 炎症会引起疾病，至少部分归因于骨髓重塑。 这项提议的首要目标是将张博士培养成一名成功的独立调查员 表观遗传血液学。从拟议的学习和职业中获得的知识和经验 发展计划将坚定地让她走上成为表观遗传血液学领先研究人员的道路。