One main consequence of numerous cardiovascular and respiratory disorders, whether in the neonate, older infant or at a later more mature age, is tissue O2 deprivation. Clinically, such a consequence can have devastating effects on especially susceptible organs such as the brain, heart and kidney. Further, it has been well demonstrated that the developing mammal responds differently to hypoxia than the mature subject, both in-vivo and in tissues in-vitro. Our overall Program hypothesis is that O2 deprivation leads to alterations in cytosolic, membrane and nuclear events that form the underlying basis for cellular adaptation, sublethal injury or cell death. The extent of these alterations depends on many factors including age, type of cell and its endowments in excitable cells (e.g. neurons) and non-excitable cells (e.g. glia, renal tubular epithelium), interactions between cells and severity and chronicity of hypoxia. The central aims of this Program will therefore be to 1) define the nature of the response to hypoxia in neurons, glia and renal tubular epithelium in mature and immature cells and 2). delineate the underlying mechanisms at the cellular and molecular level. To address these aims and determine the mechanisms that can lead to injury or adaptation in the mature and immature cell, we have formulated and devised 4 major projects that are interactive, interdependent and that share facilities (2 cores), concepts and experimental approaches. To accomplish these aims, several techniques are employed including microelectrode and patch clamp recordings, measurements of ion fluxes and intracellular ion activities, electron, immunofluorescent and confocal microscopy, Nuclear Magnetic Resonance, enzyme assays and molecular biologic techniques to study native tissue, slices, dissociated cells and excised membranes. The studies outlined in this Program represent a natural extension of work currently done by each PI. We firmly believe that this Program will provide the opportunity of enhancing the productivity of each individual project and, perhaps more importantly, the synthesis of new concepts about susceptibility to anoxia and the formulation of therapeutic modalities.
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