Mechanisms of marrow microenvironmental aging and their impact of progression of clonal hematopoiesis

骨髓微环境老化机制及其对克隆造血进展的影响

基本信息

批准号：
10539513
负责人：
MICHAEL W BECKER
金额：
$ 53.49万
依托单位：
UNIVERSITY OF ROCHESTER
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：
2022-07-15 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10539513
关键词：
Acute Myelocytic Leukemia Address Aging Area Biological Markers Biology of Aging Bone Marrow Bone marrow failure Cell Aging Cell model Cells Chronic Clinical Clonal Expansion Comb animal structure DNA Repair Data Development Dysmyelopoietic Syndromes Elderly Epigenetic Process Event Failure Functional disorder Gene Frequency Genes Genome HIV Hematopoiesis Hematopoietic Hematopoietic stem cells Heterogeneity Homeostasis Human Individual Infection Inflammation Inflammatory Interleukin-1 beta Intervention Knowledge Lead Lesion Longevity Malignant Neoplasms Marrow Mission Modeling Molecular Morbidity - disease rate Mus Mutate Mutation Myeloproliferative disease Natural Immunity Nucleotides Organism Oxidoreductase Pathology Pathway interactions Patients Persons Pharmaceutical Preparations Phenotype Play Population Process Public Health RNA Recording of previous events Regulation Reporting Repression Research Resolution Retrotransposition Retrotransposon Reverse Transcriptase Inhibitors Reverse Transcription Risk Role Stromal Cells Testing Time Translations Transplantation United States National Institutes of Health Wild Type Mouse Work age related aged bone aging cardiovascular risk factor clinical development defined contribution derepression disability epigenome experimental study genetic element genetic variant hematopoietic stem cell fate high risk improved interest leukemia loss of function macrophage middle age mortality mutant novel overexpression prevent senescence sex

项目摘要

Project Abstract Mutated clones in hematopoietic cells, also known as clonal hematopoiesis (CH) are present in healthy individuals and expand with aging. In spite of normal hematopoietic parameters, individuals with CH have increased risk of myeloid neoplasms, cardiovascular risk and all-cause mortality. We recently showed that the aged microenvironment contributes to hematopoietic stem cell fate choices. While the presence of clonal hematopoiesis in healthy individuals has been widely reported, and its expansion with aging is established, whether the aging microenvironment modifies clonal dynamics and contributes to clonal selection leading to progression to myelodysplastic syndromes (MDS) remains unexplored. Sirtuin6/SIRT6 is a regulator of genome and epigenome stability. SIRT6 is responsible for more efficient DNA repair in long-lived species. Moreover SIRT6 plays a critical role in suppressing retrotransposon expression, demonstrating that retrotransposon activity directly contributes to the progeroid phenotype in mice lacking SIRT6, in part through activation of innate immunity. Nucleotide reverse transcriptase inhibitors (NRTIs) developed as HIV drugs, inhibit retrotransposition, reduce inflammation, improve aging biomarkers in wild type mice, and extend the lifespan of progeroid mice lacking SIRT6. We hypothesize that aging-associated de-repression of retrotransposons promotes pro- inflammatory changes of specific hematopoietic stem cell-supportive niche populations (marrow macrophages and multipotent stromal cells) which drive clonal progression to myeloid neoplasms. To test this hypothesis, using relevant models of clonal hematopoiesis we will examine whether 1) pre-leukemic mutations form clones and progress to MDS more readily in the aged microenvironment by transplanting them into young versus aged recipient mice; 2) SIRT6 overexpression in key microenvironmental populations slows the rate of microenvironmental and hematopoietic aging, clonal expansion and progression to MDS; 3) repressing LINE1 retrotranspositions with inhibitors of reverse transcriptases (NRTIs) slows clonal expansion and provides a mechanism to discover novel microenvironmental regulators of clonal hematopoiesis progression.

项目摘要造血细胞中的突变克隆，也称为克隆造血（CH）个人并随着衰老而扩展。尽管有正常的造血参数，但患有CH的个体增加髓样肿瘤，心血管风险和全因死亡率的风险增加。我们最近表明老化的微环境有助于造血干细胞命运的选择。而克隆的存在健康个体中的造血症已得到广泛报道，并建立了衰老的扩张，衰老的微环境是否会修饰克隆动力学，并有助于克隆选择导致进展到骨髓增生综合征（MDS）仍未开发。 Sirtuin6/sirt6是基因组的调节器和表观基因组稳定性。 SIRT6负责长寿命物种的更有效的DNA修复。而且 SIRT6在抑制返回跨座子的表达中起着至关重要的作用直接有助于缺乏SIRT6的小鼠的后代表型，部分通过先天性激活免疫。核苷酸逆转录酶抑制剂（NRTIS）作为HIV药物开发，抑制逆转录置位，减少炎症，改善野生型小鼠的衰老生物标志物，并延长后代小鼠的寿命缺少SIRT6。我们假设与衰老相关的逆转座子的抑制会促进特异性造血干细胞支持的特定炎症变化（骨髓巨噬细胞以及驱动克隆进展到髓样肿瘤的多元基质细胞）。为了检验这一假设，使用克隆造血的相关模型，我们将检查1）白血病前突变形成克隆并通过将其移植到Young与年龄的情况下，在老年微环境中更容易地进展到MD 接受者小鼠； 2）关键微环境人群中的SIRT6过表达减慢微环境和造血衰老，克隆膨胀以及向MDS的发展； 3）压制线1 逆转录逆转录酶（NRTIS）抑制剂减慢克隆膨胀，并提供了一个，并提供了一个发现克隆造血进展的新型微环境调节剂的机制。