Recent studies suggest that the steroid hormones estrogen and progesterone, their metabolic products, andchemical derivatives mediate protection against cellular damage and death. In a variety of organs and celltypes, this has been documented for both acute insults and degenerative diseases. Among the protectivemechanisms that are triggered by these steroid hormones is the re-establishment of the cytosolic freecalcium ion homeostasis. This important gatekeeper of cellular decisions to progress towards differentiation,mitosis or apoptosis is critically dependent on the activity of intracellular calcium channels (ICC), inositol 1, 4,5-trisphosphate receptor (IP3R) and ryanodine receptors (RyR). Intracellular calcium signaling mediated bythese channels can be specifically altered by acute and chronic application of estrogen and/or progesterone.The present application will test the hypothesis that steroid hormones regulate intracellular calcium signalingthrough ICC that are important for neuronal function and viability. In particular, the effect of estrogen,progesterone, and related compounds, will be evaluated for their ability to induce posttranslationalmodifications of ICC and thereby elicit neuroprotection-related signaling pathways by controlling the cytosolicfree calcium ion homeostasis. This is of high significance due to the fact that the non-genomic effects ofestrogen and progesterone, which include intracellular calcium signaling, have the potential to provide thenecessary information to design physiologically and clinically relevant cytoprotection strategies relevant forage-related disorders affecting the nervous systems and neurodegenerative diseases including Alzheimer'sdisease (AD). The overall goal of the study is to identify novel signaling pathways that are part of nongenomicactions of estrogen and progesterone in the nervous system. This identification of novel therapeutictargets will subsequently enable us to develop new strategies in cytoprotection for pathophysiologicalprocesses affecting neurons during aging and AD.AD is affecting the health and quality of life of an increasing number of individuals. In addition, changes inhormone levels in the aging population contribute as risk factors to AD and other age-related diseases. Thepresent proposal addresses these pressing health issues that are also the focus of agency-wide NIH / NIAactivities. Results from the proposed study will enable researchers to generate more effective drugs for ADand related diseases and clinicians to utilize more effective therapeutic approaches in hormone replacementtherapy and in age related diseases including AD.
Showing the most recent 10 out of 132 publications
