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Constitutively active LH receptors in transgenic mice

转基因小鼠中持续活跃的 LH 受体

基本信息

批准号：
7184701
负责人：
PREMA NARAYAN
金额：
$ 24.66万
依托单位：
SOUTHERN ILLINOIS UNIVERSITY CARBONDALE
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-01-01 至 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7184701
关键词：
Affect Age Age-Months Biological Caliber Cell Count Cell Cycle Proteins Cell Proliferation Cells Chimeric Proteins Chronic Complex Cultured Cells Defect Development Disease Employee Strikes Endocrine Enzymes Estrogens Etiology Exhibits Female Female infertility Fertility Fertility Study Follicle Stimulating Hormone Follicular Atresia Follicular cyst Functional disorder Goals Gonadal Steroid Hormones Gonadal structure Gonadotropins Histology Hormonal Change Hormone Receptor Hormones Human Human Chorionic Gonadotropin Hyperplasia Knock-out LH Receptors Lead Ligands Luteinization Luteinizing Hormone Measurement Measures Mediating Molecular Morphology Mus Mutation Oocytes Ovarian Ovary Ovulation Pathology Personal Satisfaction Phenotype Physiological Physiology Play Precocious Puberty Prema Premature Ovarian Failure Progesterone Property Protein Kinase Proteins Receptor Activation Receptor Mediated Signal Transduction Receptor Signaling Reproduction Research Research Project Grants Role Seminiferous tubule structure Signal Pathway Signal Transduction Signal Transduction Pathway Somatic Cell Sperm Count Procedure Staging Testing Testosterone Time Transgenic Mice Transgenic Organisms Week base cell motility folliculogenesis granulosa cell inhibin insight interstitial cell leydig interstitial cell male mouse model novel promoter receptor reproductive senescence sertoli cell size tool transgene expression

项目摘要

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.

描述（由申请人提供）：本研究的长期目标是了解组成活性黄体生成素受体（LHR）表达的生殖后果。LHR在男性和女性生殖中的关键作用是由受体的激活和失活突变引起的发育和生殖缺陷所强调的。例如，人类LHR的激活突变与家族性男性限制性性早熟（FMPP）和间质细胞增生有关。转基因和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活性的轭式激素受体融合蛋白（YHR）的转基因小鼠。雄性转基因小鼠的青春期前睾丸激素水平增加，同时睾丸大小和精小管直径减小。雌性转基因小鼠在早期表现出卵泡发生增加，在3个月时，卵泡闭锁和卵泡囊肿的存在增加，这表明组成性LHR活性可能导致卵巢早衰。本研究的目的是阐明卵巢中观察到的睾丸发育改变和早期生殖衰老的内分泌和分子基础。在第一个目标中，我们将检查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消耗的影响。在第二个目标中，我们将分析LHR信号通路中激素水平和关键分子表达的时间变化，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生理学和病理生理学提供新的信息，并为FMPP、女性不育和卵巢早衰的分子机制提供新的见解。