The long term goal of this proposal is to elucidate mechanisms which are responsible for the age-related changes and for the intrinsic genetic control of the function of hematopoietic stem cells. Our preliminary data show that the activity of a progenitor cell associated autocrine loop involving transforming growth factor-beta (TGF-beta), a potent inhibitor of hematopoiesis is subject to age-related changes and is genetically determined. Therefore, we hypothesize that the inhibitory autocrine loop is induced during senescence and is one of the mediators of the developmentally regulated decrease in proliferative and repopulation capacity of stem cells, thereby protecting stem cells from critical telomere shortening. Furthermore, we hypothesize that genetically determined functional variation in the TGF-beta system is one of the factors responsible for the variation in the in vivo behavior of the stem cells among mouse strains.
The specific aims of this proposal are the following: 1. In vitro molecular and functional studies of the autocrine TGF-beta look in mice: Studies will be undertaken to determine at which molecular level (production, activation, secretion, signal transduction) the autocrine TGF- beta loop differs among mouse strains. The evolution of the autocrine (TGF-beta), loop with age will be further investigated in several inbred mouse strains. 2. To study the role of the autocrine TGF-beta loop in the biology of the murine hematopoietic system in vivo: Approaches will be used where the repopulating potential of stem cells deficient in components of the autocrine TGF-beta loop will be assessed. 3. Mapping strain-dependent differences in the autocrine TGF-beta loop. Gene mapping will be performed using appropriate sets of recombinant inbred strains.
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