Patients with ESRD are exposed to a constantly increasing plasma osmolality as urea accumulates in extracellular fluids. ESRD, particularly in children, can also commonly be associated with a variety of serious and usually episodic electrolyte and osmolality disorders such as hypernatremia. Plasma hyperosmolality and its correction can lead to serious central nervous system (CNS) complications including brain damage, coma, brain developmental disorders and even death. The underlying causes of these complications are not well understood, but changes In brain osmoregulatory metabolism are likely to play an important role. Effective treatments for the CNS complications of hyperosmolality are lacking. The brain adapts to plasma hyperosmolality by activating volume regulatory mechanisms. For example, hypernatremia results in brain shrinkage which is followed by return of the brain to its original volume. This behavior, termed regulatory volume increase (RVI), is mediated initially by uptake of electrolytes from the extracellular fluids. With chronic exposure to hypernatremia, electrolytes are replaced by organic solutes (""""""""organic osmolytes"""""""") such as inositol and amino acids. Correction of hypernatremia results in brain swelling and volume regulatory loss of electrolytes and organic solutes. Remarkably, the cellular and molecular mechanisms by which the brain adapts to hyperosmolality and its correction are largely unknown. Recently, however, we developed the first CNS cell culture models that exhibit a pattern of hyperosmolar volume regulation similar to that seen in vivo. We will utilize these models to 1) elucidate the mechanisms and control of volume regulatory electrolyte uptake and organic osmolyte loss and accumulation pathways in glial and neuronal cells 2) determine the mechanisms by which Na-dependent inositol transport is upregulated by hypernatremia, 3) characterize the osmoregulatory role of methylamine compounds in uremic brain cells, and 4) determine how volume regulatory electrolyte and organic osmolyte accumulation pathways are temporally coordinated. Studies outlined in this grant will provide the first detailed understanding of the cellular and molecular mechanisms by which cells of the CNS adapt to acute and chronic hyperosmolar disturbances and to the clinical correction of the hyperosmotic state. Investigations such as these are essential for. understanding the CNS complications of osmolality disturbances and in the development of more effective therapies to treat plasma hyperosmolality and ESRD. As such, our proposed investigations address directly several of the major objectives of the RFA.
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