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

衰老与克隆性造血(CH)有关，克隆造血是一种鲜为人知的过程，长寿的造血干细胞(HSCs)及其具有某些体细胞突变的后代经历正向选择。慢性肝炎患者罹患血癌、心血管疾病、2型糖尿病和全因死亡的风险增加。了解CH是如何和为什么随着年龄增长而发生的，并确定有效的干预措施以延长健康寿命，对于减少老年人CH相关疾病具有很大的潜力。利用DNMT3A常见CH突变的小鼠模型，我们有了一个新的发现，DNMT3A突变的HSCs在骨髓微环境中诱导基质细胞衰老。此外，我们发现，给DNMT3A突变小鼠注射靶向Bcl2/BclxL的感觉神经药物足以降低DNMT3A-HSCs在体内的选择优势。在目标1中，我们将确定DNMT3A突变的HSCs产生的特异性细胞因子和生长因子，这些细胞因子和生长因子具有体外诱导骨髓基质细胞衰老的能力。在目标2中，我们将确定DNMT3A突变的HSC本身对Bcl2/BclxL靶向感受性药物的敏感程度。这个项目的成功完成将开始完善我们对DNMT3A突变的HSC改变其微环境的机制(S)的理解，并确定敏感药物影响的细胞类型(S)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.