The cessation of reproductive function is one of the most dramatic and fairly rapid endocrine changes in the life of a female and carries profound and broad repercussions. At one time, it was thought that decreasing estradiol concentration, resulting from exhaustion of ovarian follicles, caused the menopause. Now, it is clear that many factors interact to bring about declining reproductive function and the cessation of reproductive cycles. Furthermore, we are beginning to appreciate the most- reproductive state affects multiple functions that extend beyond the traditional reproductive axis. An increasing number and an increasing proportion of women will liver a larger fraction of their lives in the postmenopausal state. Therefore, it is critical that we deepened our understanding of the factors that regulate the transition to acyclicity and, conversely, the impact of transition to acyclicity on the function of multiple systems. The program is organized into five research projects that are supported by one Core. The projects are integrated and coordinated to test the following hypotheses (1) changing estrogen responsiveness governs the health and function of ovarian follicles during aging, (2) age-related and estradiol-dependent alterations in the pattern of expression in the ovarian metalloproteinases and their inhibitors result in abnormalities in follicular development and ovulation, (3) aging and/or the cumulative exposure to estradiol regulate changes in somatotroph and lactotroph function, (4) alterations in glutamatergic and adrenergic regulation of GnRH neurons cause changes in their ability to induce LH surges; and (5) estradiol plays a critical protective role in the brain; therefore, declining estradiol concentrations lead to an increased vulnerability to brain injury and neurodegeneration. An Administrative/Animal ore supports all of the projects, providing organizational planning, integrating results from each project into a more comprehensive overview, and maintaining all animal records and coordinating their optical endocrine treatments and use. We submit this program project proposal because we share interests in interdependent aspects of reproductive aging. A common threat that weaves through all of the projects is our interests in the role of estradiol in aging. Finally, this mechanism of support will permit us to use aging animals in the most optimal manner, allowing us to compare data and economize on the costs of aging animals.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
1P01AG017164-01A1
Application #
6131828
Study Section
Special Emphasis Panel (ZAG1-PKN-2 (J1))
Program Officer
Bellino, Francis
Project Start
2000-09-30
Project End
2005-08-31
Budget Start
2000-09-30
Budget End
2001-08-31
Support Year
1
Fiscal Year
2000
Total Cost
$719,321
Indirect Cost
Name
University of Kentucky
Department
Physiology
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
Moran, Francisco M; Chen, Jiangang; Gee, Nancy A et al. (2013) Dehydroepiandrosterone sulfate levels reflect endogenous luteinizing hormone production and response to human chorionic gonadotropin challenge in older female macaque (Macaca fascicularis). Menopause 20:329-35
Rutkowsky, Jennifer M; Wallace, Breanna K; Wise, Phyllis M et al. (2011) Effects of estradiol on ischemic factor-induced astrocyte swelling and AQP4 protein abundance. Am J Physiol Cell Physiol 301:C204-12
Lam, Tina I; Wise, Phyllis M; O'Donnell, Martha E (2009) Cerebral microvascular endothelial cell Na/H exchange: evidence for the presence of NHE1 and NHE2 isoforms and regulation by arginine vasopressin. Am J Physiol Cell Physiol 297:C278-89
Brown, Candice M; Suzuki, Shotaro; Jelks, Karen A B et al. (2009) Estradiol is a potent protective, restorative, and trophic factor after brain injury. Semin Reprod Med 27:240-9
Suzuki, Shotaro; Brown, Candice M; Wise, Phyllis M (2009) Neuroprotective effects of estrogens following ischemic stroke. Front Neuroendocrinol 30:201-11
Downs, Jodi L; Wise, Phyllis M (2009) The role of the brain in female reproductive aging. Mol Cell Endocrinol 299:32-8
Brown, Candice M; Dela Cruz, Christopher D; Yang, Enhua et al. (2008) Inducible nitric oxide synthase and estradiol exhibit complementary neuroprotective roles after ischemic brain injury. Exp Neurol 210:782-7
Jelks, Karen Bozak; Wylie, Rebecca; Floyd, Candace L et al. (2007) Estradiol targets synaptic proteins to induce glutamatergic synapse formation in cultured hippocampal neurons: critical role of estrogen receptor-alpha. J Neurosci 27:6903-13
Suzuki, Shotaro; Brown, Candice M; Dela Cruz, Christopher D et al. (2007) Timing of estrogen therapy after ovariectomy dictates the efficacy of its neuroprotective and antiinflammatory actions. Proc Natl Acad Sci U S A 104:6013-8
Suzuki, Shotaro; Gerhold, Lynnette M; Bottner, Martina et al. (2007) Estradiol enhances neurogenesis following ischemic stroke through estrogen receptors alpha and beta. J Comp Neurol 500:1064-75

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