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

衰老与克隆造血（CH）有关，这是一个知之甚少的过程，长寿的造血干细胞（HSC）及其具有某些体细胞突变的后代经历正选择。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。

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.