DESCRIPTION (Scanned from the applicant's description): Estrogen is well known to play a critical role in reproduction and to have important beneficial effects on the brain. The mechanism(s) underlying these important effects of estrogen are unknown and represent the focus of this grant application. Our major hypothesis is that astrocytes function to mediate, at least in part, the reproductive and beneficial effects of estrogen on the brain. Thus, we propose that astrocytes are capable of regulating the neurosecretion, neuronal connectivity and survival of GnRH and non-GnRH neurons and that these effects are primarily due to the ability of astrocytes to release transforming growth factor-beta (TGFbeta). Central to this proposed mechanism, is the hypothesis that 17beta-estradiol exerts regulatory control over astrocytes to stimulate release of TGFbeta. This putative 17beta-estradiol-astrocyte-TGF-beta signaling pathway could have important implications not only to reproduction, but could also provide a conceptual framework to explain how estrogen may be beneficial in certain clinical situations such as stroke and Alzheimer's disease. Aim 1 would establish whether TGFbeta mediates the GnRH-releasing, neurite outgrowth and neuroprotective actions of hypothalamic astrocytes. This aim would characterize the different TGF-beta isoforms released by hypothalamic astrocytes, the degree of correlation between their levels and the functional effects of hypothalamic astrocyte-conditioned media (HA-CM), and perform causative studies to prove a role for TGFbeta. Aim 2 would characterize the recently discovered 17beta-estradiol-astrocyte-TGFbeta signaling pathway in the hypothalamus and establish the underlying mechanisms and functional implications of the pathway. This aim would determine the specific TGFbeta isoforms regulated by 17beta-estradiol, the functional importance of such regulation, whether it is ERalpha or ERbeta that mediates the 17beta-estradiol effects, and the applicability of the novel pathway to other clinically important estrogen target tissues, such as cortex and hippocampus, as well as to the human. Aim 3 will establish whether steroid hormones upregulate TGFbeta type I, II and/or III receptors in GnRH neurons during the time of the LH surge. Preliminary results showed a dramatic up-regulation of the TGFbeta type II receptor in the hypothalamus at the time of the LH surge induced by estrogen plus progesterone. This aim would confirm these preliminary observations and extend them by determining whether the up-regulation occurs in GnRH neurons, whether it is 17beta-estradiol or progesterone which is responsible for the effect, and determine if the steroid regulation extends to the type I and type III TGFbeta receptors as well. Aim 4 will establish the cell signaling mechanism utilized by HA-CM and TGFbeta to promote neurite outgrowth and exert neuroprotection on GnRH neurons. This study would examine the Ras-Raf-ERK pathway, with the hypothesis that this signaling pathway activates downstream mediators such as the neurite-outgrowth promoting factor, growth associated protein-43 (GAP-43), and the anti-apoptotic proteins bcl-2 and bcl-xl in order to promote neurite-outgrowth and survival of GnRH and non-GnRH neurons.
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