Regulation of glucocorticoid secretion is essential for maintenance of neuronal homeostasis. In normal physiology, these hormones bind to endogenous adrenocorticosteroid receptors (ACRs), through which they exert trophic actions on neurons (by way of the mineralocorticoid receptor [MR]) and serve to promote defensive responses to physiological or psychological stress (by way of the glucocorticoid receptor [GR]). The latter defensive responses are adaptive in the short run, serving to mobilize body resources. However, if release is prolonged, glucocorticoids can have multiple negative consequences for the animal. Included among these are neurotoxic effects on neurons in the hippocampus. In normal individuals, glucocorticoid release is tightly controlled, thereby maintaining subtoxic levels. Unfortunately, as a consequence of aging or Alzheimer's disease (AD), this control is lost, resulting in prolonged glucocorticoid release which has been linked with age-related hippocampal cell loss and memory deficits. Loss of the capacity to regulate glucocorticoids is a consequence of impaired stress regulation, and appears to prominently involve neuronal ACR imbalances. The present studies are designed to identify cellular mechanisms underlying ACR dysregulation in stress and aging, with the eventual goal of targeting specific pathways for prevention of glucocorticoid-related cell loss.
Specific Aim 1 will address the hypothesis that stress and glucocorticoids affect ACR gene expression and protein synthesis by the same molecular mechanism, verifying the primacy of glucocorticoids in regulating receptor synthesis in vivo.
Specific Aim 2 will characterize specific molecular pathways regulating GR and MR biosynthesis in neurons, identifying molecular targets for age-induced dysregulation.
Specific Aim 3 will evaluate the hypothesis that stress and aging work by way of the same glucocorticoid-mediated pathway to disrupt ACR regulation. Finally, Specific Aim 4 will determine whether age- and stress-induced changes in ACR regulation specifically target the neurotrophins, glucocorticoid-responsive molecules involved in maintenance of neuronal cell viability. It is predicted that the results of this project will identify specific mechanisms responsible for impaired ACR regulation in aging and AD.
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