Modulation of aged hematopoietic stem cell niches

老年造血干细胞生态位的调节

基本信息

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
项目类别：
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

项目摘要

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）：造血系统的衰老导致患有细胞质，骨髓增生综合征（MDS），骨髓增生性疾病和白血病的风险增加。 Calvi实验室和其他实验室表明，在正常的造血干细胞和祖细胞（HSPC）调节中，成骨细胞谱系细胞（骨髓微环境的关键成分）的核心作用。衰老改变了鼠模型和人类中的HSPC，减少了它们的静止和重建骨髓的能力，并被认为对整个造血系统的衰老都重要。数据开始出现支持老化微环境在HSPC衰老中的作用。但是，这尚未在人类中描述，尚不清楚利基市场的刺激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（甲状旁腺激素和前列腺素E2）的2种药理学剂迅速增加了HSPC静止并刺激体内的HSC小生裂。基于这些结果，我们假设利基的衰老有助于HSPC功能障碍，并且可以通过利基刺激来补救这些变化。在此应用程序中，我们提出了一种高度整合和翻译的方法，在这种方法中，我们将使用年轻和老年人的样本和鼠实验以及2种MD的鼠模型来验证我们的中心假设，并确定先前证明的治疗方法是否通过微环境刺激增加了HSC的使用可能会使HSPC中的hspcs和 /或 /或 /或 /或 /或 /或 /或 /或 /或 /或 /或 /或 /或 /或 /或 /或 /或 /或 /或在HSPC中相关。在这个项目中，我们将确定1）HSPC是否在衰老的情况下在衰老的环境下以及2）在衰老的情况下以及2）在衰老的情况下，2）在衰老的情况下，在衰老的情况下，在衰老的情况下，在衰老的情况下，在衰老的情况下，在衰老的情况下，在衰老的情况下，在衰老的情况下，靶向靶向细胞的靶向调制。衰老可以改善HSPC的支持并防止与MDS相关的骨髓衰竭发展。这些目标的完成将阐明一种新型的治疗策略，以逆转骨髓衰竭和对老年人白血病的敏感性。