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

基本信息

批准号：
10506906
负责人：
Christine R Zhang
金额：
$ 9万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
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/10506906
关键词：
Accounting Address Age Aging Anemia Aplastic Anemia Architecture 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 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 Inflammation Interferon Type II Knowledge Laboratories Lead Lesion Link Mentors Molecular Multipotent Stem Cells Mus Mutant Strains Mice Mutate Mutation Obesity Outcome Study Pathology Pathway interactions Phenotype Play Population Postdoctoral Fellow Prevalence Property Recurrence Research Personnel Risk Role Running Serum Signal Transduction Somatic Mutation Stress Symptoms T-Lymphocyte TP53 gene TXNIP gene Technical Expertise Techniques Testing Therapeutic Training Transplantation Universities Up-Regulation 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 expansion hematopoietic stem cell quiescence improved inflammatory milieu innovation medical schools microbial multiple omics multiplexed imaging mutant mutant mouse model overexpression pressure progenitor reconstitution response skills stem cells success transcriptome trend

项目摘要

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.

抽象的在这份独立之路奖申请中，张若超博士概述了详细的职业生涯发展计划战略性地增强她在趋势血液学方面的知识以及她在状态方面的专业知识最先进的技术，同时探究 Dnmt3a 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具有优势。张博士是华盛顿大学医学院的博士后研究员，拥有很强的研究能力。具有表观遗传学和遗传学背景，具有多种技术技能。说到这里，她想明白表观遗传干扰如何导致造血缺陷并进而导致血液疾病。初级张博士的目标是成为表观遗传血液学领域的独立研究者。张博士提出职业发展计划，她将接受非常成功的世界知名领导者的严格培训血液学，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（Daniel Link 博士）和疾病造血（Timothy Ley 博士）。她的杰出导师团队将确保她成功实现这一宏伟目标。张博士将获得1）强化 HSPC 生物学、骨髓成分和血液疾病病理学知识； 2) 专业知识单细胞水平和多重成像分析中的高级表观遗传学分析； 3）关键软技能运行一个成功且创新的独立实验室所必需的。衰老过程中 HSC 区室中获得的 DNA 甲基转移酶 3A (DNMT3A) 的体细胞突变导致导致克隆性造血（CH），这是一种与血液疾病风险增加相关的疾病。这 DNMT3A-CH (10%) 和血液疾病 (~1%) 之间的患病率不成比例，表明环境因素疾病进展的克隆选择和进化可能需要压力。累计的同时有证据表明，DNMT3A 突变可以通过慢性干扰素-γ (IFNg) 信号传导进行选择， DNMT3A 突变如何在慢性炎症期间赋予 HSC 健康优势，目前仍不清楚；如何 Dnmt3a 突变型 HSC 的扩增重塑了骨髓组成并最终导致疾病状况。本研究的目的是探究 HSC 健身优势的潜在机制 Dnmt3a 突变所传达的信息，并了解慢性病如何选择有缺陷的造血功能炎症引起的疾病至少部分归因于骨髓重塑。该提案的总体目标是将张博士培养成一名成功的独立研究者表观遗传学血液学。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者的道路。