The impact of reduction of cellular senescence on age-related epigenetic heterogeneity

细胞衰老减少对年龄相关表观遗传异质性的影响

• 批准号: 10830053
• 负责人: James V Degregori
• 金额: $ 20.13万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10830053
• 关键词: Acute Myelocytic Leukemia; Adult; Age; Aging; Automobile Driving; Bar Codes; Blood; Bone Marrow; Cardiovascular Diseases; Cell Aging; Cell secretion; Cells; Contracts; Data; Development; Disease; Elderly; Environment; Epigenetic Process; Evolution; Foundations; Gene Mutation; Health; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Heterogeneity; Immune; Inflammatory; Knowledge; Longevity; Malignant Neoplasms; Mus; Outcomes Research; Pathway interactions; Phenotype; Prevention; Prevention strategy; Production; Proliferating; Rejuvenation; Risk; Somatic Mutation; Testing; Transplantation; Wild Type Mouse; Work; age related; aged; anticancer research; bone aging; cytokine; fitness; forging; human old age (65+); interest; leukemia; novel therapeutics; post-transplant; preventive intervention; response; senescence; single-cell RNA sequencing; stem cell function; stem cells; transcriptomics

PROJECT SUMMARY This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 23-045. The decline in hematopoietic stem and progenitor cell (HSPC) function with aging can lead to improper blood and immune cell production, contributing to reduced health and life span. Aged HSPCs accumulate somatic mutations that confer a selective fitness advantage, leading to clonal hematopoiesis (CH), a blood phenotype that increases the risk of leukemia and various diseases of aging including cardiovascular diseases. Cellular senescence, a hallmark of aging, is another potent extrinsic candidate driver for age-related CH in the bone marrow microenvironment. Senescent cells secrete inflammatory factors that can influence the function and differentiation of surrounding cells, including cytokines that are crucial for driving CH. Determining the impact of reducing cellular senescence on the epigenetic heterogeneity of HSPC in aged bone marrow of mice is significant for aging and cancer research, given that greater epigenetic heterogeneity of HSPC with age should alter both stem cell functionality in hematopoiesis and increase the odds of leukemic progression. We will test the hypothesis that rejuvenating the bone marrow microenvironment by reducing senescence will reduce epigenetic heterogeneity of HSPC. This knowledge can contribute to the development of novel therapeutic and preventative strategies for mitigating age-related blood disorders, ultimately benefiting prevention of both hematopoietic decline and increased blood malignancy risk in the elderly. To follow the fate of specific subclones of HSCs, we will uniquely barcode thousands of HSC from old wildtype mice, which will be transplanted into three groups of host mice with vehicle or senolytic treatment to determine how aged vs. rejuvenated BM microenvironment influences HSPC heterogeneity. We will use scRNA-seq and snATAC-seq analysis to identify cell cluster-associated epigenetic and transcriptomic signatures and associated heterogeneity for expanded vs. contracted HSC clones. We will also identify senescence-dependent epigenetic signatures and associated heterogeneity from post-transplantation snATAC-seq data. The expected outcomes of this research will be to determine the impact of cellular senescence reduction on the epigenetic heterogeneity of HSPC in aged bone marrow of mice and identify the specific pathways that are modulated given the rejuvenated, less inflammatory microenvironment. This work can provide a mechanistic foundation for understanding the initiation of age-related blood disorders.

项目概要 本申请是为了响应被识别为 NOT-CA- 的特殊利益通知 (NOSI) 而提交的 23-045。随着年龄的增长，造血干细胞和祖细胞（HSPC）功能下降，可能导致不适当的治疗。 血液和免疫细胞的产生，导致健康和寿命缩短。老化的 HSPC 积累 体细胞突变赋予选择性适应性优势，导致克隆造血（CH），一种血液 表型会增加患白血病和各种衰老疾病（包括心血管疾病）的风险。 细胞衰老是衰老的一个标志，是年龄相关性 CH 的另一个有效的外在候选驱动因素。 骨髓微环境。衰老细胞分泌可影响功能的炎症因子 以及周围细胞的分化，包括对驱动 CH 至关重要的细胞因子。确定影响 减少细胞衰老对衰老小鼠骨髓 HSPC 表观遗传异质性的影响 鉴于 HSPC 随着年龄的增长而表现出更大的表观遗传异质性，这对于衰老和癌症研究具有重要意义 改变干细胞的造血功能并增加白血病进展的几率。我们将测试 通过减少衰老来恢复骨髓微环境的假设将减少 HSPC 的表观遗传异质性。这些知识有助于开发新的治疗方法和 减轻与年龄相关的血液疾病的预防策略，最终有利于预防这两种疾病 老年人造血能力下降，血液恶性肿瘤风险增加。追踪特定亚克隆的命运 的 HSC，我们将对来自老野生型小鼠的数千个 HSC 进行独特的条形码，将其移植到 对三组宿主小鼠进行赋形剂或 senolytic 治疗，以确定衰老与恢复活力的 BM 的情况 微环境影响 HSPC 异质性。我们将使用 scRNA-seq 和 snATAC-seq 分析来识别 细胞簇相关的表观遗传和转录组特征以及扩展与非扩展的相关异质性 收缩的 HSC 克隆。我们还将鉴定衰老依赖性表观遗传特征和相关的 移植后 snATAC-seq 数据的异质性。这项研究的预期成果将是 确定细胞衰老减少对老化骨中 HSPC 表观遗传异质性的影响 小鼠骨髓并确定在恢复活力、炎症较少的情况下受到调节的特定途径 微环境。这项工作可以为理解与年龄相关的疾病的发生提供机制基础。 血液疾病。