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.

项目摘要 该申请是为了响应特殊利益通知（NOSI）而提交 23-045。造血茎和祖细胞（HSPC）功能的下降可能导致不适当 血液和免疫细胞产生，导致健康和寿命降低。老化的HSPC积累 赋予选择性健身优势的体细胞突变，导致克隆造血（CH），血液 表型增加了白血病和包括心血管疾病在内的各种衰老疾病的风险。 蜂窝衰老是衰老的标志，是另一个有效的外部候选驱动器，用于年龄相关的CH 骨髓微环境。衰老细胞分泌可以影响功能的炎症因素 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 在小鼠老年骨髓中HSPC表观遗传异质性上减少细胞衰老 鉴于HSPC随着年龄的增长，对衰老和癌症的研究显着 改变造血中的干细胞功能，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。这些知识可以有助于新型治疗和 减轻与年龄有关的血液疾病的预防策略，最终使两者受益 老年人的造血下降和血液恶性肿瘤风险增加。遵循特定子克隆的命运 在HSC中，我们将从旧的野生型小鼠中唯一的条形码将数千种HSC进行移植到 三组宿主用媒介物或鼻溶剂治疗的宿主小鼠，以确定年龄与恢复活力的BM 微环境影响HSPC异质性。我们将使用SCRNA-SEQ和SNATAC-SEQ分析来识别 与细胞簇相关的表观遗传和转录组特征以及相关的异质性，用于扩展V。 签约的HSC克隆。我们还将确定依赖衰老的表观遗传学特征和相关的 转移后SNATAC-SEQ数据的异质性。这项研究的预期结果将是 确定细胞衰老降低对老年骨骼中HSPC表观遗传异质性的影响 小鼠的骨髓并识别给定恢复活力的调节的特定途径 微环境。这项工作可以为理解与年龄相关的启动提供机械基础 血液疾病。