Stem Cells and Aging

干细胞与衰老

• 批准号: 10394999
• 负责人: PETER J. QUESENBERRY
• 金额: $ 32.75万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394999
• 关键词: AR gene; Address; Administrative Supplement; Adult; Age; Aging; Androgen Receptor; Androgens; Area; Biological; Biology of Aging; Blood; Blood Cells; Bone Marrow; Bone Marrow Transplantation; CD34 gene; Centers of Research Excellence; Clinical; Clonal Expansion; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Development; Diagnostic; Dysmyelopoietic Syndromes; Ensure; Female; Follicle Stimulating Hormone; Follicle Stimulating Hormone Receptor; Frequencies; Gene Expression; Gene Frequency; Gene Mutation; Genes; Goals; Gonadal Steroid Hormones; Health Sciences; Heart Diseases; Hematologic Neoplasms; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; High Prevalence; Homeostasis; Hormone Receptor; Human; Immune response; In Vitro; Incidence; Individual; Knock-out; Knowledge; Lentivirus; Life; Lung diseases; Marrow; Mediating; Molecular; Mus; Mutation; National Heart, Lung, and Blood Institute; Non-Hematologic Malignancy; Pathogenesis; Patients; Play; Process; Production; Prognosis; Reporting; Research; Risk; Role; SEER Program; Sex Differences; Signal Pathway; Sleep Disorders; Somatic Mutation; Strategic Planning; Surveys; Testing; Transplantation; United States National Institutes of Health; Woman; Women' s Health; age group; age related; base; blood treatment; clinical decision-making; cohort; deep sequencing; exome sequencing; experimental study; expression cloning; genetic variant; hematopoietic gene; human old age (65+); improved; innovation; insight; interest; leukemia; male; men; men' s group; middle age; next generation sequencing; novel; peripheral blood; precision medicine; resilience; sex; sexual dimorphism; stem cell aging; therapy outcome; transcriptome; transcriptome sequencing; treatment response

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.

项目概要/摘要： 项目2的项目负责人，题为：“衰老和年龄中的造血骨髓微环境- 干细胞和衰老COBRE（1 P20 GM 119943）中的“相关白血病”正在请求行政管理 题为“中年女性骨髓微环境在衰老中的重要作用”的补编 造血”。拟议的研究涉及战略目标1“推进严格的研究， 目标1.1“发现女性和男性之间的基本生物学差异， 2019-2023年跨NIH妇女健康研究战略计划的“男性” 妇女健康”。具体而言，拟议的研究是响应感兴趣的研究领域NHLBI 对于本NOSI（NOT-GM-21-018）“确定女性对某些心脏， 肺、血液和睡眠疾病”。 对于许多与年龄有关的血液疾病，女性比男性风险更低，生存率更高。 总体而言，根据2012-2016年的调查，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 血液中的发病率、预后和治疗反应的性别差异的潜在机制 疾病仍不清楚。这方面的研究也很缺乏。因此，本提案的目的是 以确定妇女对与年龄有关的血液病的复原力的潜在机制。我们的长期 目的是阐明性别对年龄相关性血液病发病机制和治疗的影响， 女性的治疗效果。 我们最近发现，造血干细胞中造血基因表达的下降， 雌性小鼠的HSPCs在衰老过程中比雄性小鼠晚得多。我们 初步研究表明，在衰老造血中观察到的两性异形可能是由 通过性激素促卵泡激素（FSH）和雄激素信号通路。我们的首要目标 本研究旨在通过小鼠体内FSH和雄激素受体检测其潜在机制。接下来，我们假设 衰老造血中的性别二态性在人类造血基因表达方面也存在 以及HSPC的克隆扩增。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维持衰老造血中的作用 女性目标2.通过测量BM-1，证实人类衰老造血的性二态性。 衍生的CD 34 + HSPC。目标3.为了确定HSPC水平上克隆造血的差异， 不同年龄段的男女。

项目成果

The Generation and Functional Characterization of Human Microglia-Like Cells Derived from iPS and Embryonic Stem Cells.

iPS 和胚胎干细胞衍生的人类小胶质细胞样细胞的生成和功能表征。

• DOI: 10.1007/978-1-0716-3287-1_6
• 发表时间: 2023
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Lehoux,Mikael;Connolly,Kevin;Assetta,Benedetta;Huang,Yu-WenAlvin
• 通讯作者: Huang,Yu-WenAlvin

Effect of dose, dosing intervals, and hypoxic stress on the reversal of pulmonary hypertension by mesenchymal stem cell extracellular vesicles.

• DOI: 10.1177/20458940211046137
• 发表时间: 2021-10
• 期刊: Pulmonary circulation
• 影响因子: 2.6
• 作者: Klinger JR;Pereira M;Tatto MD;Dooner MS;Wen S;Quesenberry PJ;Liang OD
• 通讯作者: Liang OD

Natural Killer cell activation, reduced ACE2, TMPRSS2, cytokines G-CSF, M-CSF and SARS-CoV-2-S pseudovirus infectivity by MEK inhibitor treatment of human cells.

通过 MEK 抑制剂处理人体细胞，激活自然杀伤细胞，降低 ACE2、TMPRSS2、细胞因子 G-CSF、M-CSF 和 SARS-CoV-2-S 假病毒感染性。

• DOI: 10.1101/2020.08.02.230839
• 发表时间: 2020
• 期刊: bioRxiv : the preprint server for biology
• 作者: Zhou,Lanlan;Huntington,Kelsey;Zhang,Shengliang;Carlsen,Lindsey;So,Eui-Young;Parker,Cassandra;Sahin,Ilyas;Safran,Howard;Kamle,Suchitra;Lee,Chang-Min;Lee,ChunGeun;Elias,JackA;Campbell,KerryS;Naik,MandarT;Atwood,WalterJ;You
• 通讯作者: You

Novel use of FDA-approved drugs identified by cluster analysis of behavioral profiles.

• DOI: 10.1038/s41598-022-10133-y
• 发表时间: 2022-04-21
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Edmister, Sara Tucker;Hernandez, Thais Del Rosario;Ibrahim, Rahma;Brown, Cameron A.;Gore, Sayali, V;Kakodkar, Rohit;Kreiling, Jill A.;Creton, Robbert
• 通讯作者: Creton, Robbert

The universal stem cell.

• DOI: 10.1038/s41375-022-01715-w
• 发表时间: 2022-12
• 期刊: LEUKEMIA
• 影响因子: 11.4
• 作者: Quesenberry, Peter J.;Wen, Sicheng;Goldberg, Laura R.;Dooner, Mark S.
• 通讯作者: Dooner, Mark S.