1992 — 1995 |
Brann, Darrell W |
R29Activity Code Description: Undocumented code - click on the grant title for more information. |
Excitatory Amino Acids--Role in Gnrh, Lh &Fsh Secretion @ Medical College of Georgia (McG)
This project addresses the fundamental issue of whether excitatory amino acids (EAAs), such as glutamic acid or aspartic acid, are involved in the neuroendocrine regulation of gonadotropin secretion in the female rat. While significant work has been done in the male on this question, surprisingly little work has been performed in the female. Gaining a better understanding of the neuroendocrine events and mechanisms which regulate the gonadotropin surge in the female is important, since it could lead to new ways to regulate reproduction and to new methods for treating infertility. The proposed study will determine the ability of EAAs to regulate GnRH, gonadotropin and prolactin secretion in the female rat using both in vitro and in vivo approaches. In vitro studies will examine the ability of a variety of natural (endogenous) and synthetic EAAs to regulate GnRH release from hypothalami of estrogen-primed ovariectomized (ovx.) adult rats perfused in vitro. The specific receptor mediating each EAA effect will also be determined as will the ability of each EAA to repetitively stimulate GnRH release. EAAs will also be administered in vivo to validate that the effects observed in vitro are real effects that can be observed in the natural in vivo environment. Aim 2 will examine whether EAA effect is influenced by gonadal steroid background. Ovx. rats with and without estradiol or estradiol plus progesterone replacement will be used in this aim. Both in vitro GnRH release and in vivo LH, FSH and PRL release after EAA administration will be assessed in these animals. In Aim 3, specific NMDA and non-NMDA receptor antagonists will be employed in ovx. estrogen-progesterone treated animals, and during the different days of the cycle to determine the physiological role of EAAs in negative and positive feedback regulation. Furthermore, the role of endogenous EAAs in pulsatile GnRH and LH release in the female will also be examined. Aim 4 will determine if the effect of EAAs on GnRH, LH, FSH and prolactin release is mediated through effects on other neurotransmitter systems (catecholamine, acetylcholine and NPY) known to regulate the release of these hormones and releasing hormones. Specific antagonists to each respective system mentioned above will be utilized in vitro and in vivo to answer this question. Also, the possibility that these neurotransmitter systems could use EAAs to mediate their effect on GnRH, gonadotropin or PRL release will be examined. Aim 5 will examine whether steroids can modulate EAA receptor density and affinity in neuroendocrine tissues such as the hypothalamus using ovx. rats with and without steroid replacement, as well as cycling rats on each day of the cycle. These studies will provide important new information on the precise role of EAAs in the regulation GnRH, gonadotropin and prolactin secretion in the female.
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1 |
1996 — 2000 |
Brann, Darrell W |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. R29Activity Code Description: Undocumented code - click on the grant title for more information. |
Excitatory Amino Acids: Role in Gnrh, Lh &Fsh Secretion @ Medical College of Georgia (McG)
Significant progress within the last 5 years has established that excitatory amino acid transmitters (EAAs) play a central role in the control of GnRH neurosecretion. The renewal proposal focuses on elucidating the mechanisms utilized by EAAs to regulate GnRH secretion, and further delineating the sequence/interaction of neuroendocrine signals in the induction of the preovulatory LH surge. Aim 1 will determine the role of nitric oxide (NO) as a downstream mediator of EAA effects in the hypothalamus to control GnRH and LH secretion. The effect of EAAs on hypothalamic NO production will be evaluated as will the essential question of whether NO production is regulated by steroids and is elevated at the time of the proestrus LH surge. Aim 2 will determine whether opioid neurons function to tonically inhibit hypothalamic glutamate and/or NO neurons by examining the effect of naloxone on hypothalamic glutamate release and NO production. Aim 3 will determine the precise second messenger systems utilized by glutamate and NO to regulate GnRH and LH release. Hypothalamic expression of the second messenger, guanylate cyclase and cyclooxygenase, will be determined during the cycle and the preovulatory LH surge, and following administration of glutamate and/or NO agents. Enzyme inhibitors will also be used to determine functional significance of these systems. Aim 4 will determine whether a defect in glutamate neurosignaling is involved in reproductive aging by determining whether EAA receptors, EAA release rates and NO production are attenuated in the hypothalamus of the middle-aged rat on proestrus afternoon. Aim 5 will establish whether the enzyme heme oxygenase, which synthesizes carbon monoxide in the brain, has a physiological role in production of the LH surge and is regulated by glutamate and/or steroids. Aim 6 will establish whether steroid hormones control hypothalamic glutamate transporter expression as a mechanism of regulating glutamate levels at the synapse. These studies will enhance our understanding of the complex neuroendocrine mechanisms controlling GnRH and LH secretion in the female.
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1 |
1997 |
Brann, Darrell W |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
Excitatory Amino Acids &Brain Function--Conference @ Gordon Research Conferences
DESCRIPTION: Partial support is requested for the 1997 Gordon Research Conference to be held at Plymouth State College from June 29, through July 4, 1997. The thrust of the conference is on excitatory amino acids and brain function. The conference will include approximately 130 research investigators, including post-doctoral fellows and advanced graduate students. Specific topics to be covered include: 1) cell and molecular biology of excitatory amino acids (EAA) and their receptors; 2) EAA receptor topology and post-transcriptional modification; 3) EAA receptor signal transduction; 4) metabotropic EAA receptors; 5) role of EAAs in learning and memory; 6) role of EAAs in endocrine signaling; 7) EAAs in pathophysiologic diseases; and 8) EAAs in ischemic brain injury. The interdisciplinary nature of the conference encourages informal and open discussion among the participants, provides an environment for the development of new approaches, and allows for initiation of new collaborative efforts which could shape the future directions of this field.
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0.913 |
1998 |
Brann, Darrell W |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Effect of Progesterone On Gonadotropin Secretion @ Medical College of Georgia (McG)
Significant progress has been made during the last 5 years in elucidating the complex mechanisms involved in the stimulatory and inhibitory effects of progesterone on gonadotropin secretion. From these studies, a multifactorial hypothesis explaining regulation of gonadotropin secretion by progesterone has been proposed which includes progesterone regulation of estrogen receptor dynamics, modulation of opioid tone, and modulation of GABA and glutamate neurotransmission of the positive and negative feedback effects of progesterone. This renewal application will further elucidate mechanisms involved with the initiation and termination of the gonadotropin surge and has 4 specific aims. SPECIFIC AIM 1 will determine the mechanism of an increase in estrogen receptors of the pituitary associated with the termination of the preovulatory gonadotropin surge. The study will include measurement of pituitary ER mRNA transcription and translation along with ER binding and degradation. The role of a hypothalamic factor will also be investigated by using hypothalamic-lesioned rats, a GnRH antagonist and NPY. SPECIFIC AIM 2 will determine the role of estrogens and progesterone on the regulation of the opioid tone during the gonadotropin surge. The studies will include the measurement of hypothalamic beta-endorphin, opioid receptors and POMC mRNA levels and their correlation with gonadotropin secretion. SPECIFIC AIM 3 will determine the role of GABA in progesterone-induced inhibition and stimulation of gonadotropin secretion in the hypothalamus and the pituitary. The study will use in vitro hypothalamic GnRH release and pituitary FSH and LH release in the presence and absence of GABA agonists and antagonists and intraventricular injection of GABA antagonists. GABA receptors will also be measured. SPECIFIC AIM 4 will determine the role of glutamic acid decarboxylase (GAD) in the stimulation and suppression of gonadotropin secretion by progesterone. The study will include measurement of hypothalamic GnRH, GABA, glutamic acid, GAD activity and GAD mRNA levels during progesterone induced stimulation and suppression of gonadotropin secretion. These studies will provide new information on the neuroendocrine regulation of gonadotropin secretion by progesterone.
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1 |
1998 |
Brann, Darrell W |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Endocrine Aspects of Reproductive Biology @ Medical College of Georgia (McG) |
1 |
1999 |
Brann, Darrell W |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
Excitatory Amino Acids and Brain Function Conference @ Gordon Research Conferences
The 1999 Gordon Research Conference on Excitatory Amino Acids and Brain Function will be held at Plymouth State College from 27 June 1999 - 2 July 1999. The conference will bring together approximately 130 active investigators, post-doctoral fellows and students for discussion of recent advances in the area of excitatory amino acids (EAAs). Specific topics which will be covered at the conference include 1) ultrastructure of excitatory synapses and organization of excitatory amino acid (EAA) receptors, 2) synaptic targeting of EAA receptors and interaction with anchoring and clustering proteins, 3) genetic approaches to EAA functions, 4) role of EAAs in physiological processes, 5) role of EAAs in learning and memory, 6) EAA transporter proteins and their physiological and pathophysiological roles, and 7) EAAs in pathophysiological diseases such as Rasmussin's Encephalitis, epilepsy, brain injury, stroke and ischemic damage to brain cells. This proposal request funds to provide partial support for travel and subsistence expenses for invited participants from North America and overseas. This conference will be timely and important as it will bring together investigators from many scientific disciplines whose common link is the elucidation of the role and mechanisms of EAAs in brain function. The interdisciplinary nature of the conference, coupled with the unique Gordon Conference format, which encourages informal and open discussion among the participants, provides an idea environment for the development of new ideas/approaches, and initiation of new collaborative efforts which will help shape the future directions of this critical field.
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0.913 |
2001 — 2005 |
Brann, Darrell W |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Astrocyte-Neuron Interactions and Gnrh Neuronal Function @ Medical College of Georgia (McG)
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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1 |
2001 — 2004 |
Brann, Darrell W |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanisms of Reproductive Aging @ Medical College of Georgia (McG)
DESCRIPTION: (Scanned from the applicant's description): Despite intense investigation, the mechanisms underlying reproductive aging in females remains poorly understood. A hypothalamic defect is suggested to play a role, as prior to becoming acyclic, middle-aged rats display a significant attenuation of the proestrous LH surge and possess a significantly lower number of activated GnRH neurons in the hypothalamus. We hypothesized that the decreased activation of GnRH neurons on proestrus in the middle-aged rat could be due to a defect in the glutamate system, which is a major excitatory transmitter system regulating GnRH secretion. Our preliminary studies support this hypothesis as we demonstrated that the GnRH response to glutamate agonists is significantly attenuated in the middle-aged rat on proestrous. The mechanism responsible for the attenuated GnRH response to glutamate in the middle-aged proestrous rat remains unclear and is the primary focus of this grant. Aim 1 will use microdialysis to measure glutamate and aspartate release rates in the hypothalamus of the middle-aged and young proestrous rat in order to determine whether there is a compromised excitatory amino drive to GnRH neurons. Aim 2 will establish whether the reduced glutamate responsiveness in the middle-aged rat on proestrus could be due to an age-related reduction in ionotropic glutamate receptors in the hypothalamus. Aim 3 will examine the status of anchoring/clustering proteins for glutamate receptors (PSD95, Chapsyn-1 10, GRIP) in the middle-aged proestrous rat since a defect in these proteins would lead to ineffective synaptic targeting, clustering and anchoring of glutamate receptors, with a corresponding loss of glutamate action. Aim 4 will determine whether an age-related defect exists in the nitric oxide (NO) system in the hypothalamus, since NO is a major regulator of GnRH neuronal activation and a key mediator of glutamate effects. To prove causation between an identified defect and the attenuated LH surge, we will use retroviral gene transfer technology to correct the defect and see if this leads to reinstatement of the LH surge and extends cyclicity. As a whole, the proposed studies will provide important insights as to why glutamate signaling is compromised in the hypothalamus of the middle-aged rat, and will advance our understanding of reproductive aging.
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1 |
2005 — 2009 |
Brann, Darrell W |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neuroprotective and Neurogenic Actions of E2 and Serms @ Georgia Regents University
DESCRIPTION (provided by applicant): There is growing evidence that estrogen (E2) and SERMs may have beneficial effects upon the CNS in neurodegenerative diseases. This application would study the potential mechanisms of E2/SERM neuroprotection in cerebral ischemia, and would follow up on exciting preliminary work by our lab which suggests that E2/SERMs enhance neurogenesis following cerebral ischemia. With regards to neuroprotection, our preliminary studies suggest that E2 and the SERM, tamoxifen (TMX) inhibit activation of putative prodeath factors (ROS, ERKs, INK, c-Jun), with an increase in activation of the prosurvival factor, Akt. To confirm these preliminary findings and clarify the underlying mechanisms, Aim 1 would determine the temporal pattern and cell type of ERK/JNK/Akt activation following cerebral ischemia in female animals (which is currently lacking), establish the onset and duration of E2/SERM regulatory effects upon these key kinases, and determine the role of estrogen receptors in the regulatory effects. Aim 2 would determine whether reactive oxygen species (ROS) function as the major upstream activator of ERKs/JNK following cerebral ischemia, and establish whether E2 and TMX can suppress ROS production as a mechanism for suppression of ERK/JNK activation. Causation between ROS and ERK/JNK activation would be determined through the use of the antioxidant SOD mimetic compound, tempol (which scavenges/reduces ROS production). Aim 3 would determine whether AP-1 transcription complex and proapoptotic BH-3 proteins act downstream of ERKs/JNK to induce apoptosis in the penumbra region, and establish whether E2 and TMX suppress AP-1 activation and induction of BH-3 proteins as a means of neuroprotection. Aim 4 would characterize the temporal pattern of E2/SERM effects on neurogenesis, and characterize the migration, differentiation and long-term survival of newly generated cells into the injured regions of the brain following cerebral ischemia. Correlation to functional neurological outcomes will also be determined. As a whole, the proposed studies would significantly advance our understanding of the neuroprotective and neurogenic actions of E2 and SERMs in the injured brain.
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1 |
2010 — 2019 |
Brann, Darrell W Vadlamudi, Ratna K. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Mechanisms of Estrogen Signaling and Neuroprotection @ Georgia Regents University
DESCRIPTION (provided by applicant): 172-Estradiol (E2) has been implicated to exert neuroprotection in a variety of neurodegenerative disorders, including stroke;however, the mechanisms underlying its nongenomic and genomic signaling in the brain, and its neuroprotective effects remains unclear. Work by our group may shed light on this issue via our cloning of a novel ER coregulator, called PELP1, which we propose is the critical "missing link" that explains E2 ability to induce both nongenomic and genomic signaling in the brain and neuroprotection. To test our hypothesis, Aim 1 would use a PELP1 forebrain-specific KO (PELP1 FB KO) mouse model to determine the role of PELP1 in E2 nongenomic and genomic signaling, antioxidant actions, and neuroprotective effects in the brain following cerebral ischemia. Since little is known about the regulation of PELP1 in the brain, Aim 2 would characterize PELP1 expression, phosphorylation and signalsome formation in the brain following cerebral ischemia, determine the regulatory role of E2, and identify kinases responsible for the phosphorylation of PELP1. Preliminary data suggest that PELP1 may also play an important role in regulating local E2 production in the brain by regulating activation of the brain aromatase promoter. Thus, Aim 3 would examine the effect of PELP1 knockout on basal and E2-induced aromatase expression and activity in the brain through use of PELP1 FB KO mice, and identify the specific brain aromatase promoter regulated by PELP1. Recruitment of PELP1 to the brain aromatase promoter would also be assessed by ChIP, and the potential role of local E2 production in amplifying neuroprotection by low physiological levels of E2 would also be examined. Finally, Aim 4 would test the hypothesis that loss of E2 neuroprotective ability after a period of long-term E2 deprivation (such as occurs after menopause) is due to a brain-specific epigenetic gene silencing of PELP1 and/or ER1, and would determine whether the gene silencing is reversible and whether E2 sensitivity can be reinstated in the brain. The proposed studies have the potential to significantly advance our understanding of how E2 exerts its signaling and neuroprotective effects in the brain, and may provide a mechanistic understanding of why E2 failed to exert beneficial cardiovascular and neural effects in the WHI study, where E2 replacement was begun long after the onset of menopause. PUBLIC HEALTH RELEVANCE: Estrogen (E2) has been implicated to exert neuroprotection in a variety of neurodegenerative disorders, including stroke. This proposal would elucidate the mechanisms underlying E2 neuroprotection in the brain and potentially provide a mechanistic explanation as to why the Women's'Health Initiative (WHI) studies failed to observe beneficial effect of E2.
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0.931 |