Project: Research project

Project Details


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.
StatusNot started


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