Determinants of Myeloid Clonal Evolution

骨髓克隆进化的决定因素

• 批准号: 10591686
• 负责人: Kristen E Schratz
• 金额: $ 17.17万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-05 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591686
• 关键词: Adult; Affect; African American; Age; Aging; Applications Grants; Automobile Driving; Baltimore; Biological Markers; Blood; Chromosomes; Clinical; Clonal Evolution; Clonality; Communities; Computational Biology; DNA Damage; Data; Development; Disease; Disease Outcome; Disease Progression; Dysmyelopoietic Syndromes; Early identification; Environment; Erythrocytes; Etiology; Event; Gene Mutation; Genes; Genetic; Germ-Line Mutation; Goals; Hematologic Neoplasms; Hematological Disease; Hematopoiesis; Hematopoietic; Heritability; Individual; Inherited; JAK2 gene; Knowledge; Lead; Length; Life; Link; Longterm Follow-up; Malignant Neoplasms; Measures; Mendelian disorder; Mentors; Mentorship; Mutation; Myelodysplastic/Myeloproliferative Disease; Myelogenous; Myeloproliferative disease; Participant; Patients; Pattern; Phenotype; Phylogenetic Analysis; Polycythemia Vera; Population; Population Control; Prevalence; Prevention; Production; Publications; RNA-Directed DNA Polymerase; Reporting; Risk; Risk Factors; Role; Sampling; Solid; Syndrome; Telomerase; Telomerase RNA Component; Testing; Training; United States; Universities; Untranslated RNA; Woman; Women' s Health; Work; age related; autosome; biobank; cohort; disorder risk; gain of function mutation; genetic epidemiology; leukemia; loss of function; loss of function mutation; medical schools; mutant; novel; novel marker; novel strategies; population based; predictive marker; premature; promoter; reconstruction; response; sequencing platform; skills; specific biomarkers; stem cells; telomere; trait

PROJECT ABSTRACT Clonal hematopoiesis is acquired with aging, and in some cases, precedes the onset of both myelodysplastic and myeloproliferative disorders. However, the genetic drivers that underlie the evolution of clonal hematopoiesis and the subsequent disease risk remain poorly understood. This proposal builds on generated evidence showing that telomere length, a genetic and clinically available biomarker, predisposes to clonal hematopoiesis in Mendelian syndromes. We have also found evidence for distinct clonal hematopoiesis mutations that appear to differentially predispose to hypoplastic and myeloproliferative phenotypes. In this application, we will examine the role of telomere length in driving clonal evolution with aging in well- characterized cohorts including a Baltimore-based cohort of community-based women with a large African American subset. Additionally, we will also examine the onset and prevalence of a novel clonal hematopoiesis mutation in the telomerase reverse transcriptase gene that appears to be protective against myeloid malignancies. This K08 grant application is supported by outstanding mentors and in a strong translational environment at Johns Hopkins University School of Medicine with a detailed mentorship and training plan that focuses on genetic epidemiology and computational biology skills. The knowledge has the potential to impact current paradigms related to hematopoietic aging, myeloid clonal disease risk as well as novel biomarkers of specific disease risk and progression.

项目摘要 克隆性造血是随着年龄的增长而获得的，在某些情况下，在两种骨髓增生异常的发病之前 和骨髓增生性疾病。然而，克隆人进化的遗传驱动因素 造血和随后的疾病风险仍然知之甚少。此建议书建立在生成的 有证据表明，端粒长度，一种遗传的和临床上可用的生物标志物，易于克隆 孟德尔综合征的造血功能。我们还发现了明显的克隆性造血的证据。 突变似乎不同地倾向于发育不良和骨髓增殖性表型。在这 应用，我们将研究端粒长度在井中随年龄增长而驱动克隆进化的作用。 具有特征的队列，包括巴尔的摩的社区女性队列和一个大型非洲人 美国子集。此外，我们还将检查一种新的克隆性造血的发病和流行情况。 端粒酶逆转录酶基因突变似乎对髓系细胞有保护作用 恶性肿瘤。这份K08奖助金申请得到了杰出导师的支持，并以强大的翻译能力 约翰霍普金斯大学医学院的环境，以及详细的指导和培训计划， 专注于遗传流行病学和计算生物学技能。这一知识具有潜在的影响 目前与造血老化、髓系克隆性疾病风险以及新的生物标志物相关的研究范式 特定的疾病风险和进展。