This is a compefing renewal application of the Program Project Grant entified "INTEGRATIVE CONSEQUENCES OF HYPOXIA". The overall focus of the Program confinues to examine the effects of systemic, cellular and molecular responses to chronic intermittent hypoxia (CIH). The overarching hypotheses of the competing renewal applicafion are: a) ROS affect chemo reflex funcfion by recruifing disfinct cellular rriechanisms in the individual components of the chemo refiex pathway (sensor, controller, and end organ);and b) Long-term exposure to CIH leads to stable changes in ROS as well as cardio- respiratory functions and involves epigenetic regulation of redox homeostasis in the chemo refiex pathway. PROJECT 1 will test the hypothesis that the effects of CIH on the carotid body are due to ROS-mediated imbalance between inhibitory (carbon monoxide;CO) and excitatory (hydrogen sulfide;H2S) gaseous messengers. PROJECT 2 tests the hypothesis that chemo reflex triggered sympathetic activation by CIH evokes oxidative stress in the adrenal medulla, a major sympathetic end organ resulfing in augmented catecholamine secretion by hypoxia, which contributes to ClH-induced hypertension. PROJECT 3 tests the hypothesis that the ClH-induced irregular breathing is mediated by carotid body-dependent ROS generation and reconfigurafion of the respiratory neural network in the PreBotC. PROJECT 4 tests the hypothesis that epigenetic regulation of genes encoding redox regulatory enzymes in the chemo refiex pathway contributes to persistent oxidative stress, and the cardio-respiratory responses to long-term CIH. CORE A fulfills an administrative and coordinating function. CORE B provides centralized facilities for exposure of rodents to CIH, maintenance of genetically modified mice, morphological, biochemical and molecular biological assays for all four projects. Because of the tight thematic linkages across the projects, the total knowledge gained from the overall program will truly be greater than the sum derived from each project.
Recurrent apnea with chronic intermittent hypoxia (CIH) is a major clinical problem affecting - 1 8 million adults in the USA alone. Our studies on rodent models revealed that CIH leads to breathing abnormalities, hypertension and elevated oxidative stress. This proposal examines systemic, cellular, and molecular mechanisms contribufing to cardio-respiratory changes by CIH.
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