Developing Effective Approaches to Extend Hematopoietic Healthspan by Targeting Cell-Extrinsic and Cell-Intrinsic Alterations at Middle Age

通过针对中年细胞外在和细胞内在的改变来开发延长造血健康寿命的有效方法

• 批准号: 10771727
• 负责人: Jennifer Jean Trowbridge
• 金额: $ 10万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10771727
• 关键词: Age; Aging; Automobile Driving; BCL2L1 gene; Blocking Antibodies; Blood; Bone Marrow; Cardiovascular Diseases; Cell Senescence Induction; Cells; Colony-Forming Units Assay; DNMT3a; Data; Disease; Dose; Drug Targeting; Flow Cytometry; Goals; Growth Factor; Health; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Human; Individual; Intervention; Knowledge; Laboratories; Mus; Mutant Strains Mice; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Pathology; Pharmaceutical Preparations; Phenotype; Population; Process; Public Health; Research; Risk; Somatic Mutation; Specificity; Stromal Cells; System; Testing; Therapeutic Intervention; Tissues; age related; aged; cell type; cytokine; effective intervention; healthspan; hematopoietic stem cell aging; in vivo; middle age; mortality; mouse model; mutant; novel; premature; protein expression; senescence; therapeutic target

Aging is associated with clonal hematopoiesis (CH), a poorly understood process by which long-lived hematopoietic stem cells (HSCs) and their progeny with certain somatic mutations undergo positive selection. Individuals with CH have increased risk of developing blood cancer, cardiovascular disease, type 2 diabetes, and all-cause mortality. Understanding how and why CH occurs with aging, and defining effective interventions to extend healthspan, have strong potential to reduce CH-associated diseases in aged individuals. Using a mouse model of a common CH mutation in DNMT3A, we have made a novel discovery that Dnmt3a-mutant HSCs induce senescence of stromal cells in the bone marrow (BM) microenvironment. Further, we found that administering a Bcl2/BclxL-targeting senolytic drug to Dnmt3a-mutant mice was sufficient to reduce the selective advantage of Dnmt3a-HSCs in vivo. In Aim 1, we will determine the specific cytokines and growth factors produced by Dnmt3a-mutant HSCs that have the capacity to induce senescence of BM stromal cells ex vivo. In Aim 2, we will determine the extent to which Dnmt3a-mutant HSCs themselves are sensitive to Bcl2/BclxL-targeting senolytic drugs. Successful completion of this project will begin to refine our understanding of the mechanism(s) by which Dnmt3a-mutant HSCs modify their microenvironment and define the cell type(s) impacted by senolytic drugs to limit CH.

衰老与克隆性造血（CH）有关，这是一个人们知之甚少的过程，长寿的造血干细胞（HSCs）及其具有某些体细胞突变的后代通过该过程经历正选择。CH患者患血癌、心血管疾病、2型糖尿病和全因死亡的风险增加。了解CH如何以及为什么随着年龄的增长而发生，并确定有效的干预措施来延长健康寿命，对减少老年人CH相关疾病具有很大的潜力。使用DNMT 3A中常见CH突变的小鼠模型，我们已经做出了一个新的发现，即Dnmt 3a突变的HSC诱导骨髓（BM）微环境中基质细胞的衰老。此外，我们发现向Dnmt 3a突变小鼠施用Bcl 2/BclxL靶向衰老清除药物足以降低Dnmt 3a-HSC在体内的选择性优势。在目的1中，我们将确定由Dnmt 3a突变型HSC产生的特异性细胞因子和生长因子，其具有体外诱导BM基质细胞衰老的能力。在目标2中，我们将确定Dnmt 3a突变型HSC本身对Bcl 2/BclxL靶向衰老清除药物敏感的程度。该项目的成功完成将开始完善我们对Dnmt 3a突变型HSC修饰其微环境的机制的理解，并定义受衰老药物影响的细胞类型以限制CH。