Modulation of aged hematopoietic stem cell niches

老年造血干细胞生态位的调节

• 批准号: 9305821
• 负责人: MICHAEL W BECKER
• 金额: $ 19.19万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9305821
• 关键词: Adipocytes; Adolescent; Age; Aging; Area; Blood; Blood Cells; Bone Development; Bone Diseases; Bone Marrow; Cell Aging; Cell Lineage; Cell physiology; Cells; Clinic; Clinical; Data; Defect; Dinoprostone; Dysmyelopoietic Syndromes; Elderly; Failure; Functional disorder; Gene Expression; Goals; Health; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Hemorrhage; Hormonal; Human; Human Biology; Impairment; In Vitro; Individual; Infection; Laboratories; Marrow; Methods; Modeling; Mus; Myelogenous; Myeloproliferative disease; Orthopedic Procedures; PTH gene; Pancytopenia; Patients; Pharmacology; Phenotype; Predisposition; Production; Recovery; Regulation; Research; Risk; Role; Sampling; Secondary to; Specimen; Stem cells; Supporting Cell; Technology; Testing; Tissues; Transfusion; Translations; age effect; age related; aged; base; bone; cell age; cytopenia; experimental study; improved; in vivo; intravital microscopy; leukemia; mouse model; novel; novel therapeutics; prevent; programs; public health relevance; reconstitution; repaired; therapeutic target; translational approach; volunteer

DESCRIPTION (provided by applicant): Aging of the hematopoietic system results in an increased risk of developing cytopenias, Myelodysplastic syndromes (MDS), myeloproliferative disorders and leukemias. The Calvi laboratory and others have demonstrated the central role of osteoblastic lineage cells, a critical component of the marrow microenvironment, in normal hematopoietic stem and progenitor cell (HSPC) regulation. Aging changes HSPCs in both murine models and humans, decreasing their quiescence and their ability to reconstitute the marrow, and is thought to contribute importantly to aging of the whole hematopoietic system. Data are beginning to emerge supporting a role of the aging microenvironment on HSPC aging. However, this has not been described in humans, and it is unknown whether stimulation of the niche will reverse or mitigate the effects of aging. We have recently demonstrated that 2 pharmacologic agents which stimulate the marrow microenvironment (Parathyroid hormone and Prostaglandin E2) rapidly increase HSPC quiescence and stimulate the HSC niche in vivo. Based on these results, we hypothesize that aging of the niche contributes to HSPC dysfunction and that these changes can be remediated by niche stimulation. In this application, we propose a highly integrated and translational approach in which we will use young and aged human samples and murine experiments as well as 2 murine models of MDS to verify our central hypothesis and determine if use of treatments previously demonstrated to increase HSCs through microenvironmental stimulation can remediate age-dependent changes in the niche and /or in HSPCs. In this project we will determine if 1) HSPCs become dysfunctional in the setting of aging as a result of the aging niche and 2) targeted modulation of niche cells in the context of aging can improve HSPC support and prevent progression to MDS-related bone marrow failure. Completion of these aims will elucidate a novel therapeutic strategy to reverse marrow failure and susceptibility to leukemia in older adults.

描述（由申请人提供）：造血系统的老化导致发生血细胞减少症、骨髓增生异常综合征（MDS）、骨髓增殖性疾病和白血病的风险增加。卡尔维实验室和其他实验室已经证明了成骨细胞谱系细胞（骨髓微环境的关键组成部分）在正常造血干细胞和祖细胞（HSPC）调节中的核心作用。衰老会改变小鼠模型和人类的 HSPC，降低它们的静止状态和重建骨髓的能力，并且被认为对整个造血系统的衰老有重要贡献。越来越多的数据开始支持衰老微环境对 HSPC 衰老的影响。然而，这在人类中尚未得到描述，并且尚不清楚刺激生态位是否会逆转或减轻衰老的影响。我们最近证明，刺激骨髓微环境的 2 种药物（甲状旁腺激素和前列腺素 E2）可快速增加 HSPC 静止状态并刺激体内 HSC 生态位。基于这些结果，我们假设生态位老化导致 HSPC 功能障碍，并且这些变化可以通过生态位刺激来修复。在本申请中，我们提出了一种高度集成和转化的方法，其中我们将使用年轻和老年的人类样本和小鼠实验以及两种MDS小鼠模型来验证我们的中心假设，并确定使用先前证明通过微环境刺激增加HSC的治疗是否可以修复生态位和/或HSPC中年龄依赖性的变化。在这个项目中，我们将确定 1) HSPC 是否因衰老生态位而在衰老环境中变得功能失调，以及 2) 在以下情况下对生态位细胞进行有针对性的调节： 衰老可以改善 HSPC 支持并防止进展为 MDS 相关的骨髓衰竭。这些目标的完成将阐明一种新的治疗策略，以逆转老年人的骨髓衰竭和白血病易感性。