Aging stem cells and their microenvironment

衰老干细胞及其微环境

• 批准号: 6949891
• 负责人: GARY VAN ZANT
• 金额: $ 28.12万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6949891
• 关键词: aging; apoptosis; bioinformatics; cell migration; cell proliferation; flow cytometry; gene expression; genetic regulation; genetically modified animals; hematopoietic stem cells; laboratory mouse; longitudinal animal study; microarray technology; quantitative trait loci; telomerase; telomere; transfection /expression vector

DESCRIPTION (provided by applicant): Most, if not all, of the body's organ systems show the effects of aging. It is now increasingly apparent that homeostatic maintenance of organ function owes to cellular renewal derived ultimately from stem cells. Therefore, aging stem cells may critically impact maintenance of normal organ function. Adult stem cells, in all organs studied, rely on micro environmental cues from supporting stroma to modulate, if not direct, stem cell replication, differentiation and quiescence. This proposal investigates the effect of aging on both stem cells and the microenvironment. Using hematopoietic stem cells as a model, we test the hypothesis that the number of stem cells available in bone marrow affects that organ's capacity to supply blood and immune cells during aging. Quantitative trait loci (QTL) affecting natural variation in stem cell numbers in mice have been mapped and congenic strains have been generated in which independent effects of the loci can be studied. Efforts underway to identify the genes responsible for the QTL will identify molecular pathways important in regulating stem cell numbers and the effect of aging on them. Effects of age on the stem cell microenvironment will focus on two essential functions. The first is to capture stem cells from the circulating blood. Stem cells are in a natural state of flux between the marrow and blood with evidence that this pathway is bidirectional. Homing of stem cells to the marrow is the first critical step in stem cell transplantation in the treatment of hematologic and non-hematologic malignancies. As more and older patient's become candidates for transplant, the effects of age on homing are largely unexplored. Lastly, clinical science has found ways to dramatically alter the flux of stem cells from the marrow microenvironment into the blood in a process called mobilization. Despite its widespread use in harvesting stem cells for transplantation, the basic mechanisms are not only incompletely understood, the effects of aging are uncharted. We will use mouse models to test the hypothesis and the flux of stem cells both to and from the marrow is altered in aging.

描述（由申请人提供）：大多数（如果不是全部）身体器官系统都显示出衰老的影响。现在越来越明显的是，器官功能的稳态维持归功于最终源自干细胞的细胞更新。因此，衰老的干细胞可能严重影响正常器官功能的维持。在所有研究的器官中，成体干细胞都依赖支持基质的微环境线索来调节（如果不是直接的话）干细胞复制、分化和静止。该提案研究了衰老对干细胞和微环境的影响。使用造血干细胞作为模型，我们检验了这样的假设：骨髓中可用的干细胞数量会影响该器官在衰老过程中供应血液和免疫细胞的能力。影响小鼠干细胞数量自然变异的数量性状基因座（QTL）已经被绘制出来，并且已经产生了同源品系，其中可以研究基因座的独立影响。正在进行的鉴定负责 QTL 的基因的工作将鉴定在调节干细胞数量和衰老对其影响方面重要的分子途径。年龄对干细胞微环境的影响将集中在两个基本功能上。第一个是从循环血液中捕获干细胞。干细胞在骨髓和血液之间处于自然流动状态，有证据表明该途径是双向的。干细胞归巢到骨髓是干细胞移植治疗血液和非血液恶性肿瘤的第一个关键步骤。随着越来越多的老年患者成为移植候选者，年龄对归巢的影响在很大程度上尚未被探索。最后，临床科学已经找到了方法，可以在称为动员的过程中显着改变干细胞从骨髓微环境进入血液的流量。尽管它广泛用于采集干细胞进行移植，但其基本机制不仅不完全清楚，而且衰老的影响也是未知的。我们将使用小鼠模型来检验这一假设，并且干细胞进出骨髓的流量会随着衰老而改变。