DESCRIPTION (provided by applicant): There is a fundamental gap in understanding how aging process alters mitochondrial gene expression in health and disease. It is well known that cardiovascular functions are markedly depressed following trauma-hemorrhagic shock despite fluid resuscitation. Since mitochondrial functions are also depressed under those conditions, information concerning the age related alterations in mitochondrial gene expression after shock will be useful in understanding the role of aging and mitochondrial genes in cardiac impairment and potentially devising appropriate intervention strategies. Our long-term goal is to determine the molecular basis of the age-associated alteration of cardiac mitochondrial genes following shock and trauma. Our central hypothesis is that trauma-hemorrhagic shock leads to age- specific pathological alterations in the mitochondrial gene expression in the heart, which can be determined in an experimental model using a mitochondrial gene chip. The objective of this proposal is to develop and validate a rodent mitochondrial gene chip and use it to determine the alteration in the cardiac mitochondrial gene expression in a rat model of trauma-hemorrhagic shock. This objective will be achieved by pursuing the following three specific aims: (1) develop a rodent mitochondrial gene chip, RoMITOchip, to determine age related mitochondrial gene expression changes in an experimental model of trauma-hemorrhagic shock, ( 2) validate the RoMITOchip using (i)in vitro models of rat and mouse cardiomyocytes subjected to hypoxic and normoxic conditions, (ii) mice with inherent alteration in mitochondrial function;and (3) determine the role of aging in mitochondrial gene expression profile in the normal rat and a rat model of trauma-hemorrhagic shock using RoMITOchip. The small number of genes on the mitochondrial genome is not represented in the Affymetrix rat or mouse GeneChip. The RoMITOchip, our focused array, will include genes from the nuclear genome that contribute to the mitochondrial structure and function as well as the genes on the mitochondrial DNA, together called as mitochondrial genes. We will incorporate mitochondrial genes of the rat and the mouse into the single gene chip, RoMITOchip, and plan to use this tool to determine cardiac mitochondrial gene expression changes following trauma-hemorrhage in the young adult and aged rats. Thus the proposed research is relevant to that part of NIH's mission that pertains to developing fundamental knowledge that will potentially help to reduce the burdens of human disease. The proposed research will be significant in the context of aging and cardiac dysfunction in trauma-hemorrhage, because it is expected to develop a tool and use it to elucidate the mitochondrial gene expression profile in the aging heart following trauma-hemorrhage.Narrative The successful accomplishment of the objectives of this proposal would elucidate age related changes in mitochondrial gene expression in the heart after trauma-hemorrhage and the gene chip that will be developed as part of this project will have a broader use in aging and cardiovascular research.
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