Stem Cells and Aging

项目摘要/摘要： 项目2项目负责人：《老龄化时期的造血骨髓微环境-- 干细胞和老年病中的相关白血病(1P20GM119943)要求行政管理 副刊：《中年女性骨髓微环境在衰老中的关键作用》 造血功能“。拟议的研究涉及战略目标1“推进严格的研究，即 与妇女健康有关“，目标1.1”发现妇女和妇女之间的基本生物学差异 《2019-2023年跨美国国立卫生研究院妇女健康研究战略计划》 具体地说，拟议的研究是对NHLBI感兴趣的研究领域作出反应 对于这份nosi(非GM-21-018)《确定女性对某些心脏的复原力的潜在机制， 肺部、血液和睡眠疾病“。 在许多与年龄相关的血液疾病中，女性比男性风险更低，生存更好。 总体而言，根据2012-2016年的一项调查，骨髓增生异常综合征的男性/女性发病率比为1.9 监测、流行病学和最终结果计划(SEER)数据。然而，细胞和分子 导致血液发病率、预后和治疗反应的性别差异的机制 疾病仍不清楚。这方面的研究也很少，这也是值得注意的。因此，这项提议的目标是 确定女性对年龄相关血液疾病的潜在复原力的潜在机制。我们的长期合作 目的是阐明性别对年龄相关性血液疾病的发病机制和治疗的影响，以期改善 女性的治疗结果。 我们最近发现，在造血干细胞中，造血基因表达的下降 雌性小鼠的祖细胞(HSPC)在衰老过程中出现的时间比雄性小鼠要晚得多。我们的 初步研究表明，在衰老的造血过程中观察到的性别二型性可能是由 通过性激素、卵泡刺激素(FSH)和雄激素信号通路。我们的首要目标是 这里是在小鼠身上测试FSH和雄激素受体的潜在机制。接下来，我们假设一个 在人类的造血基因表达方面，衰老的造血中也存在性别二型性 HSPC的克隆性扩增。结合起来，我们提出了以下具体目标：目标1.确定 促卵泡激素和雄激素信号通路在衰老维持造血中的作用 女性。目的2.通过调查BM-1来证明人类衰老造血的性别二型性。 CD34+HSPC。目的3.检测不同性别人群在HSPC水平上的克隆性造血功能差异 不同年龄段的女性和男性。

Project Summary/Abstract: The Project Leader of Project 2 entitled: "Hematopoietic Bone Marrow Microenvironment in Aging and Age- related Leukemia" within the Stem Cells and Aging COBRE (1P20GM119943) is requesting an Administrative Supplement entitled: “The Pivotal Role of Middle-aged Female Bone Marrow Microenvironment in Aging Hematopoiesis”. The proposed research addresses the Strategic Goal 1 “Advancing rigorous research that is relevant to the health of women”, Objective 1.1 “Discover basic biological differences between females and males” of the 2019-2023 Trans-NIH Strategic Plan for Women's Health Research "Advancing Science for the Health of Women". Specifically, the proposed research is responsive to the Research Areas of Interest to NHLBI for this NOSI (NOT-GM-21-018) “Identification of mechanisms underlying women's resilience for certain heart, lung, blood, and sleep diseases”. Female sex is associated with less risk and better survival than male sex for many age-related blood diseases. Overall, male/female incidence ratio in myelodysplastic syndromes is 1.9 based on a survey of the 2012-2016 Surveillance, Epidemiology, and End Results Program (SEER) data. However, the cellular and molecular mechanisms underlying sex differences in the incidence, prognosis, and treatment responses of the blood disorders remain unclear. The paucity of studies in this area is also notable. Hence, the objective of this proposal to identify potential mechanisms underlying women's resilience for age-related blood diseases. Our long-term goal is to elucidate sex-effects on the pathogenesis and treatment of age-related blood diseases for an improved therapeutic outcome for women. We have recently discovered that a decline of hematopoietic gene expression in hematopoietic stem and progenitor cells (HSPCs) of female mice occurs much later in the aging process than that of male mice. Our preliminary study suggests that the observed sexual dimorphism in aging hematopoiesis may be mediated through the sex hormone follicle-stimulating hormone (FSH) and androgen signaling pathways. Our first objective here is to test the potential mechanisms with FSH and androgen receptors in mice. Next, we hypothesize that a sexual dimorphism in aging hematopoiesis also exists in humans with regard to hematopoietic gene expression and clonal expansion of the HSPCs. Combined, we propose the following specific aims: Aim 1. To determine the role of follicle-stimulating hormone and androgen signaling pathways in sustaining hematopoiesis in aging females. Aim 2. To demonstrate a sexual dimorphism of aging hematopoiesis in humans by surveying BM- derived CD34+ HSPCs. Aim 3. To determine the differences in clonal hematopoiesis on the HSPC level between women and men in different age groups.