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Neuroendo Signal Transduction in Reproductive Physiology

生殖生理学中的神经内信号转导

基本信息

批准号：
7194293
负责人：
KAREN Ann GREGERSON
金额：
$ 26.85万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-01-01 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7194293
关键词：
3,4-Dihydroxyphenylacetic Acid Animals Anterior Pituitary Gland Anterior Pituitary Hormones Attention Breeding Bromocriptine Cyclic AMP Cytology DRD2 gene Daily Defect Disease Dominant-Negative Mutation Domperidone Dopamine Drops Estrogen Replacements Estrogens Estrous Cycle Event Exhibits Failure Family Female Female infertility Fertility Funding GIRK1 subunit, G protein-coupled inwardly-rectifying potassium channel GTP-Binding Proteins Generations Genetic Transcription Growth Hormones Hyperplasia Hypothalamic structure In Vitro Ion Channel Lactation Lead Measures Membrane Messenger RNA Mining Modeling Molecular Mus Neurosecretory Systems Partner in relationship Pathology Pathway interactions Phase Physiological Pituitary Gland Play Positioning Attribute Potassium Potassium Channel Pregnancy Production Proestrus Prolactin Property Proteins Regulation Reproduction Reproductive Physiology Reproductive Process Research Personnel Role Serum Signal Transduction Syndrome System Technology Testing Time Transcript Transgenes Transgenic Mice Transgenic Model Transgenic Organisms Wild Type Mouse Withdrawal Woman adenoma base design and construction gain of function in vitro Assay insight inward rectifier potassium channel loss of function median eminence member mouse model mutant physical property promoter receptor research study size

项目摘要

DESCRIPTION (provided by applicant): Prolactin (PRL), an anterior pituitary hormone, has profound effects on female fertility. Hypersecretion of PRL is the major neuroendocrine-related pathology associated with female infertility. Isolated PRL deficiency, while rare, also results in reduced fertility and lactational failure in women. The underlying defects which lead to the common hypersecretion of PRL remain ill-defined, as do many of the mechanisms involved in the normal regulation of episodic PRL release. Usually, PRL secretion is under tonic inhibition by hypothalamic dopamine (DA). Periodic, physiological surges of PRL in females require a withdrawal from this dopaminergic inhibition. The fact that reduced responsiveness to DA is a hallmark of hyperprolactinemic syndromes demanded that we focus our attention on the cellular and molecular basis of DA action on the lactotrope. We have discovered and extensively characterized a DA-activated inwardly-rectifying potassium channel (KDA) in normal female lactotropes. DA regulates lactotrope membrane excitability through activation of KDA and in vitro studies have demonstrated a critical role for this KDAchannel in the regulation of PRL release by DA. Furthermore, the functional expression of KDAis dependent upon estrogen, which may explain a long-recognized modulatory action of estrogen on this system. In these regards, the KDA channel occupies a primal position in the hierarchy of events in dopaminergic regulation of PRL secretion. We have proposed to evaluate the role of this effector K channel within its physiological context - the whole animal through transgenic technology. To this end, we have designed and constructed "dominant negative" mutants, capable of inhibiting wild-type KDA function in lactotropes. We then created a transgenic mouse model ("Loss of Function") in which expression of this mutant is directed to pituitary lactotropes using the PRL promoter. A second transgenic model ("Gain of Function") has also been produced in which a constitutively active K channel, with the same biophysical properties as KDA, is over expressed in the lactotropes. Both models exhibit altered PRL secretory activity. These two models will enable us to study the physiological role of KDAand membrane excitability in the regulation of both basal and episodic release of PRL. Such studies will ultimately provide insight into the basis of secretory disorders in PRL, a hormone at the core of mammalian fertility, gestation and lactation.

描述（申请人提供）：催乳素（PRL）是一种垂体前叶激素，对女性生育能力有深远的影响。PRL的高分泌是与女性不育相关的主要神经内分泌相关病理。孤立的PRL缺乏症虽然罕见，但也会导致妇女生育能力下降和泌乳失败。导致PRL普遍高分泌的潜在缺陷仍然不明确，许多参与正常调节发作性PRL释放的机制也不明确。通常，PRL的分泌受到下丘脑多巴胺（DA）的强直抑制。女性PRL的周期性生理激增需要从这种多巴胺能抑制中退出。对DA的反应性降低是高泌乳素血症综合征的一个标志，这一事实要求我们将注意力集中在DA作用于乳糖的细胞和分子基础上。