Pharmacological rejuvenation of aged hematopoietic stem cells.

描述(申请人提供)：大多数西方国家的人口发展预测，与年龄相关的疾病及其预防将成为一个重要的社会、经济和医学话题。体细胞活性是组织再生的关键。 随着年龄的增长，造血、肠道和肌肉干细胞的质量会持续下降，损害组织的动态平衡和再生。从幼年和老年动物中获取的造血干细胞(HSCs)显示出数量上的差异，这在一定程度上是HSCs固有的。衰老的HSC表现出自我更新活动减少。衰老也会影响造血干细胞的分化潜能。许多研究表明，衰老的HSC缺乏支持红系生成的能力，不能有效地产生B淋巴系后代，但更善于支持髓系细胞系。据推测，随着年龄的增长，HSC质量下降至少部分是导致老年人贫血、免疫功能受损和髓系白血病发病率增加的根本原因，所有这些都构成了一个重大的医学问题。小的Rho家族GTP酶CDc42在调节HSCs中起着关键作用。对人类长寿的全基因组关联研究最近发现，CDC42是单核造血细胞中最高的过度表达基因，与发病率和衰老有关。重要的是，新型化合物酪蛋白对衰老HSCs中CDC42活性的药理抑制使按时间顺序老化的HSCs的功能恢复年轻。因此，我们将关注的产品/程序是酪蛋白，一种特异性的CDC42活性抑制剂，可以恢复按时间顺序老化的HSC的功能。这是一种新颖和创新的方法，因为它是第一批逆转干细胞衰老的靶向药物疗法之一。 与公共卫生相关：干细胞活动对组织和器官再生至关重要。随着年龄的增长，造血、肠道和肌肉干细胞的质量会不断下降，破坏组织的动态平衡和再生，这对老年人来说是一个重大的医学问题。在这项应用中，我们将专注于开发一种原理证明，即通过一种化合物Casin抑制造血干细胞中的小Rho GTP酶CDc42，使其成为一种新的产品，以恢复按时间顺序老化的造血干细胞的功能。这项令人兴奋的技术可能会预防或治疗与年龄相关的血液产生功能下降，从而造福老年人的生活。

DESCRIPTION (provided by applicant): The demographic development in most Western countries predicts that age-associated diseases and their prevention will become an important social, economic and medical topic. Somatic stem cell activity is critical for tissue regeneration. There is a successive age-dependent functional decline in hematopoietic, intestinal and muscle stem cell quality, impairing tissue homeostasis and regeneration. Hematopoietic stem cells (HSCs) harvested from young and aged animals show quantitative differences that are in part intrinsic to HSCs. Aged HSCs show reduced self-renewal activity. Aging also affects the differentiation potential of HSCs. Many studies have demonstrated that aged HSCs are deficient in their ability to support erythropoiesis and do not efficiently generate B-lymphoid progeny but are better at supporting the myeloid cell lineage. It is assumed that the decreased HSC quality with age is at least in part the underlying cause of anemia, impaired immune function and increased incidence of myeloid leukemia in the elderly, all of which pose a significant medical problem. The small Rho family GTPase Cdc42 plays a critical role in regulating HSCs. Genome-wide association studies of human longevity have recently identified Cdc42 as the top over- expressed gene in mononuclear hematopoietic cells associated with morbidity and aging3. Importantly, pharmacological inhibition of Cdc42 activity in aged HSCs by the novel compound CASIN rejuvenates the functional of chronologically aged HSCs. Thus the product/procedure that we will focus on is that CASIN, a specific inhibitor of Cdc42 activity, may rejuvenate the function of chronologically aged HSCs. This is a novel and innovative approach as it is among the first targeted pharmacological therapies reverting aging of stem cells. PUBLIC HEALTH RELEVANCE: Stem cell activity is critical for tissue and organ regeneration. There is a successive age-dependent functional decline in hematopoietic, intestinal and muscle stem cell quality, impairing tissue homeostasis and regeneration, which pose a significant medical problem in the elderly. In this application we will focus on developing a proof of principle, inhibition of the small Rho GTPase Cdc42 in hematopoietic stem cells by a chemical compound CASIN, into a novel product to rejuvenate the function of chronologically aged hematopoietic stem cells. This exciting technology may prevent or treat age-related functional decline of blood production to benefit the lives of older adults.