The objective of this application is to elucidate factors governing peripheral sympathetic nerve remodeling in the mature rodent uterus. Our published studies show that sympathetic nerve density of the virgin rat uterus fluctuates throughout the estrous cycle, a 4.5 day interval that is analogous to the human menstrual cycle. Nerve density is highest during diestrus and declines through estrus in association with rising plasma estrogen. Our preliminary experiments suggest that: 1) NGF mRNA and protein are also reduced at estrus, 2) estrogen administration decreases sympathetic nerve density, and 3) mice lacking a functional estrogen receptor alpha have uteri that are grossly hyperinnervated. We hypothesize that rising plasma estrogen suppresses uterine neurotrophic factor production resulting in clinical sympathetic nerve degeneration followed by regeneration.
The specific aims are: 1) Characterize the structural changes in nerves occurring during the cyclical changes in uterine sympathetic innervation, 2) determine the estrous cycle hormonal factors that mediate changes in nerve density, 3) determine if uterine neurotrophic factors that induce sympathetic neuritogenesis vary during the estrous cycle 4) determine if exogenous estrogen or other hormones affect neurotrophin expression 5) determine if estrogen-mediated changes in sympathetic neuron neurotrophin receptor expression may also contribute to the neuroplasticity, 6) determine if antibodies that selectively block neurotrophin activity can prevent uterus-mediated sprouting in vitro, 7) determine the role of the estrogen receptor alpha on nerve and uterus using the ERKO mouse, and 8) assess the functional consequences of uterine sympathetic nerve remodeling.
These aims will be accomplished using immunohistochemistry, in situ hybridization histochemistry, qualitative and quantitative RT-PCR, electron microscopy, enzyme-linked immunoassays, organ culture, and pharmacological analyses of neuroeffector transmission. These studies will provide new and important information on mechanisms underlying nerve remodeling in normal physiological conditions. This information may be important in advancing our understanding of the mechanisms regulating innervation in health and disease, and may have direct applicability to the understanding of dysmenorrhea and autonomic dysfunction that occurs in menopause.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039570-03
Application #
6477171
Study Section
Special Emphasis Panel (ZRG1-MDCN-7 (01))
Program Officer
Edwards, Emmeline
Project Start
1999-12-01
Project End
2003-11-30
Budget Start
2001-12-01
Budget End
2002-11-30
Support Year
3
Fiscal Year
2002
Total Cost
$235,998
Indirect Cost
Name
University of Kansas
Department
Physiology
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Mónica Brauer, M; Smith, Peter G (2015) Estrogen and female reproductive tract innervation: cellular and molecular mechanisms of autonomic neuroplasticity. Auton Neurosci 187:1-17
Hasan, Wohaib; Smith, H Jesse; Ting, Alison Y et al. (2005) Estrogen alters trkA and p75 neurotrophin receptor expression within sympathetic neurons. J Neurobiol 65:192-204
Blacklock, Audrey D; Cauveren, Jamie A; Smith, Peter G (2004) Estrogen selectively increases sensory nociceptor innervation of arterioles in the female rat. Brain Res 1018:55-65
Blacklock, A D; Smith, P G (2004) Estrogen increases calcitonin gene-related peptide-immunoreactive sensory innervation of rat mammary gland. J Neurobiol 59:192-204
Krizsan-Agbas, D; Pedchenko, T; Hasan, W et al. (2003) Oestrogen regulates sympathetic neurite outgrowth by modulating brain derived neurotrophic factor synthesis and release by the rodent uterus. Eur J Neurosci 18:2760-8
Hasan, Wohaib; Pedchenko, Tetyana; Krizsan-Agbas, Dora et al. (2003) Sympathetic neurons synthesize and secrete pro-nerve growth factor protein. J Neurobiol 57:38-53
Krizsan-Agbas, D; Smith, P G (2002) Estrogen modulates myometrium-induced sympathetic neurite formation through actions on target and ganglion. Neuroscience 114:339-47
Smith, Peter G; Warn, J Donald; Steinle, Jena J et al. (2002) Modulation of parasympathetic neuron phenotype and function by sympathetic innervation. Auton Neurosci 96:33-42
Zoubina, Elena V; Smith, Peter G (2002) Distributions of estrogen receptors alpha and beta in sympathetic neurons of female rats: enriched expression by uterine innervation. J Neurobiol 52:14-23
Zoubina, E V; Smith, P G (2001) Sympathetic hyperinnervation of the uterus in the estrogen receptor alpha knock-out mouse. Neuroscience 103:237-44

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