Pharmacological rejuvenation of aged hematopoietic stem cells.
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AbstractDESCRIPTION (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 showquantitative 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.
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