Lineage Determination and Tissue HomeOstasis in the aged Hematopoietic System

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DESCRIPTION (provided by applicant): Hematopoiesis involves the tightly coordinated process of blood cell production and is maintained by a small number of hematopoietic stem cells (HSCs). Compared to the young, the elderly show a substantial decline of baseline functions and adaptive capacity in various tissues and organs, including the hematopoietic system. It is assumed that these changes in hematopoiesis with age comprise one of the underlying causes for anemia and reduced immune function in the elderly, especially under stress. Resolving the number of HSCs and their progeny that actively contribute to hematopoiesis and tracking the contribution of individual HSCs to each of the different blood cell lineages is an important step to determine the cellular basis for decreased efficiency in tissue homeostasis. The primary goal of this study is to determine, on a clonal level, the cellular and molecular basis for decreased efficiency in hematopoiesis upon aging, with the long-term goal to translate this knowledge into therapies to ameliorate or even revert unwanted age-associated phenotypes in the hematopoietic system. We will use the novel technology of clonal barcoding of individual murine HSCs by short-term (4 hours) transduction (ex vivo) with self-inactivating lentiviral vectors to individually mark a multitude of HSCs to determine clonality, lineage determination and cell turnover in the hematopoietic system and the changes in these parameters associated with aging.