Aging stem cells and their microenvironment

描述（由申请人提供）：大多数，如果不是全部，身体的器官系统显示老化的影响。现在越来越明显的是，器官功能的稳态维持归功于最终来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。成体干细胞，在所有研究的器官中，依赖于来自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，我们测试的假设，即骨髓中可用的干细胞的数量影响器官的能力，在衰老过程中提供血液和免疫细胞。影响小鼠干细胞数量自然变异的数量性状基因座（QTL）已被定位，并产生了同类品系，其中可以研究基因座的独立影响。正在进行的鉴定QTL的基因的努力将确定在调节干细胞数量和衰老对它们的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。第一种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，有证据表明这种途径是双向的。干细胞归巢至骨髓是干细胞移植治疗血液系统和非血液系统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的候选人，年龄对归巢的影响在很大程度上是未知的。最后，临床科学已经找到了方法，可以显著改变干细胞从骨髓微环境进入血液的流量，这一过程称为动员。尽管它广泛用于收集干细胞用于移植，但其基本机制不仅不完全了解，衰老的影响也是未知的。我们将使用小鼠模型来验证这一假设，并且干细胞流入和流出骨髓的流量会随着年龄的增长而改变。

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.