The impact of increased mutation burden on promoting clonal hematopoiesis

突变负担增加对促进克隆造血的影响

• 批准号: 10535364
• 负责人: Chiraag Deepak Kapadia
• 金额: $ 4.71万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-24 至 2024-09-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10535364
• 关键词: Ablation; Address; Adult; Affect; Age; Aging; Behavior; Blood; Blood Cells; Bone Marrow; Cardiovascular Diseases; Cells; Clonal Expansion; Clonality; Code; DNA Damage; Development; Elderly; Environmental Risk Factor; Frequencies; Future; Genes; Goals; Health; Heart Diseases; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Human; Individual; Knock-out; Knockout Mice; Laboratory mice; Life; Literature; Longevity; Lung diseases; MGMT gene; MSH2 gene; Mammals; Measures; Modeling; Mus; Mutagens; Mutate; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Predisposition; Prevalence; Reporting; Risk; Role; Somatic Mutation; Time; Transplantation; Wild Type Mouse; Work; age effect; aged; blood fractionation; conditional knockout; driver mutation; exome sequencing; experience; experimental study; fitness; healthy aging; imprint; leukemia; middle age; mortality; mouse model; mutant; normal aging; novel; peripheral blood; repaired; targeted sequencing; temozolomide

PROJECT SUMMARY/ABSTRACT Somatic mutations occur in hematopoietic stem cells (HSCs) throughout life. By chance, a mutation may disrupt a key gene and confer a competitive advantage on the mutant HSC, leading to expansion of its clonal progeny. This phenomenon is called clonal hematopoiesis (CH) and is ubiquitous with increasing age. CH is associated with elevated risk for hematological malignancy, cardiovascular and pulmonary diseases, type II diabetes, and overall all-cause mortality. Nearly all adults older than 50 years harbor CH clones with mutations in leukemia- associated genes, but these mutant clones comprise a very low fraction of total blood cells and thus are speculated to be functionally inert. A growing body of literature indicates that, in most individuals, low-frequency mutant clonal blood fractions remain stable over time. However, no models exist that capture the behavior of these stochastically arising low-frequency clones. Thus, whether driver mutation acquisition and adequate time will lead to eventual clonal expansion remains unknown. The goal of this proposal is to determine the extent to which underlying HSC mutation burden and acquisition of CH drivers are sufficient for clonal expansion over time. Preliminary calculations predict every coding gene is mutated about 70 times in the HSC pool during an average human lifespan, indicating mutation in a CH driver gene is inevitable with longevity. In contrast, native CH has never been reported in murine models, possibly because mice have fewer HSCs and a limited lifespan during which to acquire HSC mutations. The central hypothesis of this proposal is that clonal hematopoiesis emergence is the product of sufficient mutation rate and time. I will evaluate this hypothesis using two murine models for stochastic mutation acquisition. Experiments proposed in Aim 1 will query aged wild-type mice to determine the extent that advanced age, independent of lifespan, promotes the development of CH. In Aim 2, I will experimentally elevate the global mutation burden in murine HSCs to determine if the stochastic acquisition of a CH driver mutation will lead to mutant clonal expansion over time, and how an aged milieu impacts CH development. The experiments will define the sufficiency of mutation burden and time for promoting clonal hematopoiesis and will determine the role of an aged microenvironment in clonal expansion. Overall, this work may uncover strategies to enhance healthy aging via modulation of mutant clonal outgrowth.

项目摘要/摘要 造血干细胞(HSCs)在一生中都会发生体细胞突变。一次偶然的机会，突变可能会扰乱 一个关键基因，并赋予突变的HSC竞争优势，导致其克隆后代的扩张。 这种现象被称为克隆性造血，随着年龄的增长，这种现象随处可见。CH已关联 血液系统恶性肿瘤、心血管和肺部疾病、II型糖尿病的风险增加，以及 总的全因死亡率。几乎所有50岁以上的成年人都有白血病突变的CH克隆- 相关基因，但这些突变克隆在总血细胞中所占比例非常低，因此 推测它在功能上是惰性的。越来越多的文献表明，在大多数人中，低频 突变的克隆性血液组分随着时间的推移保持稳定。然而，不存在任何模型来捕捉 这些随机产生的低频克隆。因此，司机突变的获取和充足的时间 会不会导致最终的克隆扩张仍未可知。这项提案的目标是确定以下方面的程度 哪些潜在的HSC突变负担和CH驱动程序的获取足以进行克隆扩展 时间到了。初步计算预测，在HSC池中，每个编码基因在一个 人类的平均寿命，这表明CH驱动基因的突变是长寿不可避免的。相比之下，原生的 在小鼠模型中从未报道过CH，可能是因为小鼠的HSCs较少，寿命有限 在此期间获得HSC突变。这一提议的中心假设是克隆性造血 出现是足够的突变率和时间的产物。我将用两只小鼠来评估这一假设 随机突变获取模型。目标1中提出的实验将询问老化的野生型小鼠 确定与寿命无关的高龄在多大程度上促进先天性心脏病的发展。在目标2中，我 将在实验中提高小鼠HSCs的全局突变负担，以确定随机获取 CH驱动程序突变的发生将导致突变克隆随着时间的推移而扩展，以及老化的环境如何影响CH 发展。实验将确定促进克隆的突变负担和时间的充分性。 并将决定衰老微环境在克隆扩增中的作用。总体而言，这项工作 可能会发现通过调节突变的克隆性副产物来促进健康衰老的策略。