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.
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