Species comparison of stem cell aging

描述（由申请人提供）：在新发现的和数量不断增长的哺乳动物器官中，废细胞的补充是一个共同的主题。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，与体型和寿命无关。是什么机制策略和适应性使得同样大小的干细胞群体能够补充人类比小鼠大几千倍的成熟细胞群体，而人类的寿命比小鼠长40倍？本研究的第一个目的是确定这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。将对2月龄和24月龄小鼠的骨髓干细胞进行平行比较。在衰老过程中，这些参数的物种间相似性和差异性将为细胞水平上的生理机制提供洞见。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。来自人类和小鼠的造血干细胞，无论是年轻的还是年老的，都将通过细胞分选纯化。每个干细胞群体中表达的基因库将通过从纯化群体中提取RNA并分别在微阵列上将其与人类和小鼠的基因集杂交来确定。干细胞衰老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的衰老过程中被开启、增加或维持，但在小鼠中却没有，这表明可能解释了在人类的长寿命中维持干细胞功能的候选基因。那些在两个物种中以平行模式表达变化的基因表明，保守的基因对应对衰老的严酷至关重要。那些随着年龄增长而在小鼠中表达下降的基因，而在人类中却没有，这表明可能是负责维持干细胞功能寿命的候选基因。衰老过程中干细胞的基因表达模式将揭示决定寿命的重要分子途径，并可能为治疗包括癌症在内的年龄相关疾病提供干预的分子靶点。

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.