Species comparison of stem cell aging

描述(由申请人提供)：补充用过的细胞是新发现的和数量不断增加的哺乳动物器官的共同主题。在大多数情况下，干细胞终生为这一过程提供动力。最近的证据表明，动物的造血干细胞的绝对数量是保守的，与身体大小和寿命无关。在人类的寿命是老鼠的40倍的情况下，什么样的机制策略和适应能让相同大小的干细胞群体补充成熟细胞群体，而人类的成熟细胞群体比老鼠的大几千倍？这项提议的第一个目标将确定这两个物种从年轻到老年干细胞数量、细胞周期状态、对细胞因子的反应性和凋亡率的变化。新生儿的脐带血干细胞将与75岁以上的人的骨髓干细胞进行比较。2月龄和24月龄小鼠的骨髓干细胞将进行平行比较。衰老过程中这些参数的种间相似性和差异性将为在细胞水平上采用的生理机制提供洞察。第二个目标将确定在分子水平上采用的相似和不同的种间策略。人类和小鼠的造血干细胞，无论是年轻的还是老年的，都将通过细胞分选得到纯化。通过从纯化的干细胞群体中提取RNA，并将其分别与人和小鼠的基因组杂交，在微阵列上确定每个干细胞群体中表达的基因的谱系。干细胞老化过程中基因表达的比较物种分析有望揭示几种特别感兴趣的模式。这些基因的表达在人类衰老过程中被激活、增加或保持，但在小鼠中不表达，这表明可能是人类在较长寿命内维持干细胞功能的候选基因。那些在两个物种中表达变化平行的基因表明，保守的基因对于应对严酷的衰老至关重要。那些在老鼠身上的表达随着年龄的增长而下降的人，而不是人类，表明了负责维持干细胞功能长寿的候选者。干细胞在衰老过程中的基因表达模式将揭示决定寿命的重要分子途径，并可能建议干预包括癌症在内的与年龄相关的疾病的分子靶点。

DESCRIPTION (provided by applicant): The replenishment of spent cells is a common theme in a newly appreciated and growing number of mammalian organs. In most cases, stem cells fuel this process over a lifetime. Recent evidence suggests that an animal's absolute number of hematopoietic stem cells is conserved, and is irrespective of body size and lifespan. What mechanistic strategies and adaptations allow the same-sized population of stem cells to replenish mature cell populations that in the human are several thousand-fold larger than those in the mouse, over a lifespan that is forty-fold longer in humans than in mice? The first aim of this proposal will determine the changes in stem cell number, cell cycle status, responsiveness to cytokines, and apoptosis rate from young to old age in both species. Human umbilical cord blood stem cells from newborns will be compared to bone marrow stem cells from humans greater than 75 years old. A parallel comparison will be made between bone marrow stem cells of 2 month old and 24 month old mice. Inter-species similarities and differences in these parameters during aging will provide insight to the physiological mechanisms employed at the cellular level. The second aim will determine the similar and contrasting inter-specific strategies employed at the molecular level. Hematopoietic stem cells from both humans and mice, at young and old age, will be purified by cell sorting. The repertoire of expressed genes in each stem cell population will be determined by extracting RNA from the purified populations and hybridizing it to gene sets of human and mouse, respectively, on microarrays. Comparative species analysis of gene expression during aging of stem cells is expected to reveal several patterns of special interest. Those genes whose expression is turned on, increased, or maintained during aging in human, but not in the mouse, suggest candidates that might account for maintenance of stem cell function over a long lifespan in humans. Those whose expression changes in a parallel pattern in both species suggests conserved genes fundamentally important for dealing with the rigors of aging. Those whose expression declines with age in the mouse, but not the human, suggests candidates that are responsible for the maintenance of the longevity of stem cell function. Patterns of gene expression in stem cells during aging will reveal molecular pathways important in defining longevity and may suggest molecular targets of intervention in the treatment of age-related disorders, including cancer.