Constitutively active LH receptors in transgenic mice

描述（由申请人提供）：本研究的长期目标是了解组成性活性促黄体激素受体（LHR）表达的生殖后果。LHR在男性和女性生殖中的关键作用通过受体中的激活和失活突变引起的发育和生殖缺陷来强调。例如，人类LHR中的激活突变与家族性男性限制性早熟（FMPP）和Leydig细胞增生相关。转基因和基因敲除小鼠模型促进了我们对激素和受体的正常和病理生理功能的理解。为了研究慢性配体介导的LHR活性的后果，我们产生了表达具有组成性活性的偶联受体融合蛋白（YHR）的转基因小鼠。雄性转基因小鼠产生增加的青春期前睾酮水平，伴随着睾丸大小和曲细精管直径的减少。雌性转基因小鼠在早期表现出卵泡发生增加，在三个月时，卵泡闭锁增加，卵泡囊肿的存在表明组成性LHR活性可能导致卵巢早衰。本研究的目的是阐明睾丸发育改变和卵巢早期生殖衰老的内分泌和分子基础。在第一个目标中，我们将研究睾丸和卵巢形态学和组织学的发育变化，并确定慢性LHR激活对睾丸体细胞发育和卵母细胞耗竭的影响。在第二个目标中，我们将分析激素水平的时间变化和LHR信号通路中关键分子的表达，以确定睾丸和卵巢表型的内分泌和分子基础。这些研究将为睾丸和卵巢的生理学和病理生理学提供新的信息，并为FMPP，女性不孕症和卵巢早衰的分子机制提供见解。

DESCRIPTION (provided by applicant): The long-term goals of this research are to understand the reproductive consequences of expression of constitutively active luteinizing hormone receptors (LHR). The critical role of LHR in male and female reproduction is underscored by the developmental and reproductive defects resulting from activating and inactivating mutations in the receptor. For example, activating mutations in human LHR are associated with familial male-limited precocious puberty (FMPP) and Leydig cell hyperplasia. Transgenic and knockout mouse models have facilitated our understanding of normal and pathophysiological functions of hormones and receptors. To examine the consequences of chronic ligand-mediated LHR activity, we have generated transgenic mice expressing a yoked hormone-receptor fusion protein (YHR) with constitutive activity. Male transgenic mice produce increased prepubertal levels of testosterone, accompanied by decreased testicular size and diameter of the seminiferous tubules. Female transgenic mice exhibit increased folliculogenesis at early ages, and at three months there is increased follicular atresia and the presence of follicular cysts suggesting that constitutive LHR activity may result in premature ovarian failure. The goals of this proposal are to elucidate the endocrine and molecular basis for altered testicular development and early reproductive senescence observed in the ovary. In the first aim we will examine the developmental changes in testicular and ovarian morphology and histology and determine the effect of chronic LHR activation on testicular somatic cell development and oocyte depletion. In the second aim we will analyze the temporal changes in hormone levels and expression of key molecules in the LHR signaling pathways to determine the endocrine and molecular basis of the testicular and ovarian phenotype. These studies will contribute new information on testicular and ovarian physiology and pathophysiology and provide insight into the molecular mechanisms of FMPP, female infertility and premature ovarian failure.