A central problem in genetics is how substantial shifts in the overall gene expression programs of individual cells are achieved during development and in adult cells when they adapt homeostatically to a disturbance. As a framework against which to investigate this problem, we propose a """"""""two-state"""""""" hypothesis, which we will test in relation to the complex homeostatic shifts in gene expression program that accompany the development and regression of left ventricular cardiac hypertrophy, an important cardiovascular risk factor independent of hypertension. The hypothesis states that adult cells (such as cardiac myocytes) when stressed sufficiently can switch without cell division to an alternative state in which the expression of many genes differ co-ordinately. ? ? Specific aim i) will test whether individual cardiac myocytes switch expression of representative genes coordinately between two states, and whether the degree of hypertrophy is mediated by the proportion of cells in the two states. ? ? Specific aim ii) will increase the stringency of the tests by using a much broader panel of discriminators with several categorically different ways of inducing hypertrophy, and will also test whether the hypertrophic cells replicate the expression pattern of normal cells at an earlier stage of development. ? ? Specific aim iii) will test the hypothesis that the expression programs of cardiac myocytes in the hypertrophic state can under appropriate circumstances switch back to the normal state in animals in vivo, or in tissue culture ex vivo. ? ? Our proposal is, to our knowledge, the first attempt to formalize how complex shifts in gene expression programs are achieved in cells responding to homeostatic challenges, but the value of the proposed experiments does not depend on the correctness of the two-state hypothesis since each specific aim also addresses a gap in current knowledge related to cardiac hypertrophy.
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