Blood stem cell aging and biomarker studies

 描述（由申请人提供）：关于系统性衰老的机制，已经提出了许多理论，遗传、行为和环境因素都可能参与其中。过去十年积累的证据已经发现，从成年到老年，干细胞活性的可测量和连续的年龄依赖性下降影响自然衰老期间的组织稳态。识别指示干细胞衰老的生物标志物并理解衰老干细胞在功能上变得与年轻干细胞相似的机制对于监测衰老和设计组织稳态和组织再生中与衰老相关的失衡的治疗是重要的。造血干细胞（HSC）在个体的生命周期中持续提供成熟的血细胞，这一过程称为造血。老年人免疫反应的进行性降低和骨髓恶性肿瘤的发病率增加以及贫血被认为与HSC老化有关。HSC衰老的分子机制尚不清楚，阻碍了寻找有用的生物标志物，减缓或逆转HSC功能随年龄的下降，改善衰老后的生活质量的合理方法。在造血中识别有效的衰老生物标志物将有助于诊断和治疗与年龄相关的血液状况和疾病。我们实验室发表的工作表明，在小鼠模型中，HSC在衰老时失去极性，这一现象与干细胞内在的细胞内酶Cdc 42的年龄依赖性升高以及经典Wnt 3A到非经典Wnt 5A信号转导开关有关。我们的数据进一步表明，该Wnt 5a-Cdc 42信号传导轴的遗传和药理学靶向在功能上使老化的HSC恢复活力。有趣的是，已发表的全基因组关联研究发现，Cdc 42在外周血细胞中的表达与人类的发病率和死亡率密切相关，我们的初步数据表明，在人类HSC中，随着年龄的增长，Cdc 42在外周血细胞中的活性与献血者的年龄呈正相关，这意味着Cdc 42可能是造血中衰老的有效生物标志物和/或有效靶标。在目前的研究中，我们提出了综合的实验和观察策略，以寻求我们的新的信号转导开关在HSC，Wnt 5A-Cdc 42，在单个干细胞水平的HSC的衰老表型的因果关系，包括骨髓淋巴谱系失衡和老年相关的干细胞自我更新和移植的减少，使用国家的最先进的小鼠模型。我们将进一步研究以Cdc 42信号传导轴为靶点的潜力，Cdc 42信号传导轴是衰老中HSC极性调节的关键，用于几种HSC衰老表型的年轻化。我们的研究将在动物模型中建立一种新的血液干细胞衰老机制，这种机制可以转化为人类衰老，并可能在其他干细胞系统和组织/器官再生中具有价值。

 DESCRIPTION (provided by applicant): A number of theories have been proposed regarding the mechanisms of systemic aging, and genetic, behavioral and environmental factors may all be involved. Evidence accumulated over the past decade has found measurable and successive age-dependent decline in stem cell activity from adulthood to old age to affect tissue homeostasis during natural aging. Identifying biomarkers indicative of stem cell aging and understanding mechanisms under which aged stem cells become functionally similar to young stem cells are important for monitoring aging and devising treatments for aging-associated imbalance in tissue homeostasis and tissue regeneration. Hematopoietic stem cells (HSCs) continuously provide mature blood cells during the lifespan of individuals in a process termed hematopoiesis. A progressive reduction in the immune response in the elderly and an increased incidence of myeloid malignancy, as well as anemia is thought to be linked to HSC aging. Molecular mechanism of HSC aging remain unclear, hindering rational approaches to identify useful biomarkers and to slow or reverse the decline of HSC function with age and to improve the quality of life upon aging. Identifying valid biomarkers of aging in hematopoiesis will assist n diagnosis and treatments for age- related blood conditions and diseases. Published work from our labs indicates that in mouse models, HSCs lose polarity upon aging, a phenomenon associated with stem cell intrinsic age-dependent elevation of an intracellular enzyme, Cdc42, and a canonical Wnt3A to non-canonical Wnt5A signaling switch. Our data further demonstrates that genetic and pharmacologic targeting of this Wnt5a-Cdc42 signaling axis functionally rejuvenates aged HSCs. Interestingly, published genome-wide association studies have found that Cdc42 expression in peripheral blood cells is closely linked to morbidity and mortality in humans, and our preliminary data demonstrate apolarity in human HSCs upon aging and a positive correlation between Cdc42 activity in peripheral blood cells and age of the blood donor, implying that Cdc42 might be a valid biomarker and/or valid target of aging in hematopoiesis. In the present studies, we propose integrated experimental and observational strategies to seek a causal relationship of our novel signaling switch in HSCs, Wnt5A-Cdc42, with aging phenotypes of HSCs at the single stem cell level, including myeloid-lymphoid lineage imbalances and the aged associated reduction of stem cell self-renewal and engraftment, using state-of-the-art mouse models. We will further examine the potential of targeting the Cdc42 signaling axis, key for HSC polarity regulation in aging, for rejuvenation of several HSC aging phenotypes. Our studies will establish a new mechanism of blood stem cell aging in animal models that could be translated to human aging, and may have values in other stem cell systems and tissue/organ regeneration.