Species comparison of stem cell aging

描述（由申请人提供）：消耗细胞的补充是最近受到重视且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，干细胞在一生中为这一过程提供燃料。最近的证据表明，动物的造血干细胞的绝对数量是保守的，并且与身体大小和寿命无关。什么样的机制策略和适应机制使得同样大小的干细胞群体能够补充成熟细胞群体，而人类的成熟细胞群体比小鼠的成熟细胞群体大几千倍，人类的寿命比小鼠长四十倍？该建议的第一个目的是确定两个物种从年轻到老年的干细胞数量，细胞周期状态，对细胞因子的反应性和凋亡率的变化。来自新生儿的人类脐带血干细胞将与来自75岁以上人类的骨髓干细胞进行比较。将在2月龄和24月龄小鼠的骨髓干细胞之间进行平行比较。在老化过程中这些参数的物种间的相似性和差异将提供洞察在细胞水平上采用的生理机制。第二个目标将确定在分子水平上采用的相似和对比的种间策略。年轻和年老的人类和小鼠的造血干细胞将通过细胞分选纯化。将通过从纯化的群体中提取RNA并将其分别与微阵列上的人和小鼠的基因组杂交来确定每个干细胞群体中表达基因的库。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。那些在人类衰老过程中表达被打开、增加或维持的基因，而在小鼠中则没有，这表明可能解释人类干细胞功能在长寿命中维持的候选基因。那些在两个物种中以平行模式表达变化的基因表明保守的基因对于应对衰老的严峻性至关重要。那些在小鼠中表达随着年龄的增长而下降，但在人类中不下降的人，表明候选人负责维持干细胞功能的寿命。衰老过程中干细胞中的基因表达模式将揭示定义长寿的重要分子途径，并可能提示干预治疗年龄相关疾病（包括癌症）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.