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

骨髓微环境衰老机制及其对克隆造血进展的影响

• 批准号: 10665803
• 负责人: Laura M Calvi
• 金额: $ 53.49万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 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/10665803
• 关键词: Acceleration; 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; DNA Repair; DNMT3a; 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; Lesion; Longevity; Macrophage; 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; Preleukemia; Process; Public Health; RNA; Recording of previous events; Regulation; Reporting; Repression; Research; Resolution; Retrotransposition; Retrotransposon; Reverse Transcriptase Inhibitors; Reverse Transcription; Risk; Role; Sirtuins; 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; middle age; mortality; mutant; novel; overexpression; prevent; progression risk; risk prediction; senescence; sex

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