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Characterization of KISS1R, a G protein Coupled Receptor in Reproduction

生殖中 G 蛋白偶联受体 KISS1R 的表征

基本信息

批准号：
9069913
负责人：
Le Min
金额：
$ 13.8万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9069913
关键词：
Affect Agonist Arrestins Binding Biological Cell Culture Techniques Clinical Couples Development Disease Dynorphins Endocrine System Diseases Endocytosis Experimental Designs Family member Fasting Fertility Functional disorder G-Protein-Coupled Receptors Generations Genetic Genetic Counseling Glutamates Gonadal Steroid Hormones Gonadotropin Hormone Releasing Hormone Gonadotropins Histology Hormonal Human Biology Hypothalamic structure In Vitro Infertility KISS1 gene Knock-in Mouse Lead Learning Ligands Mediating Modeling Mus Mutation Neurokinin B Neurons Neurosecretory Systems Pathway interactions Patients Phenotype Physiology Pituitary Hormones Play Precocious Puberty Process Puberty Public Health Recycling Regulation Reproduction Research Research Personnel Role Serum Signal Pathway Signal Transduction Site Stress System Therapeutic Intervention Time Training desensitization experience extracellular gain of function mutation human disease improved in vivo insight loss of function mutation mouse model new therapeutic target novel novel diagnostics novel therapeutics receptor reproductive reproductive development reproductive function response small molecule therapeutic target tool trafficking

项目摘要

DESCRIPTION (provided by applicant): The activation of gonadotropin-releasing hormone (GnRH) neurons at puberty is not well understood but recent evidence suggests a role for the kisspeptin-KISS1R system as a key regulator of reproductive development and function. While it is clear that kisspeptin and KISS1R function as essential regulators of the neuroendocrine cascade, many questions remain about the role of this novel ligand-receptor system in the regulation of GnRH neuronal function at the time of puberty as well as during subsequent reproductive function. The overarching hypothesis underlying this project is that intracellular signal transduction by kisspeptin is influenced by desensitization, internalization, and recycling/degradation of the KISS1R, thereby playing critical roles in controlling the timing of puberty and maintaining cyclical reproductive function. An additional hypothesis for this project is that a better understanding of the mechanisms by which mutations affect the kisspeptin-KISS1R system will have clinical implications by providing insights into the pathophysiology of the associated phenotypes, laying the groundwork for the development of new diagnostic tools as well as for genetic counseling of patients and their family members, and identifying novel therapeutic targets. We propose the following specific aims: (1) To characterize KISS1R-mediated intracellular signaling, trafficking, turnover, desensitization, and resensitization; (2) To identify extracellular co-factors that modulate KISS1R signaling and to study their mechanisms of action in the regulation of kisspeptin-mediated KISS1R activation; and (3) To generate and characterize a KISS1R (R386P) knock-in mouse as a model to better understand the mechanisms by which this mutation is associated with central precocious puberty (CPP). The successful completion of the proposed studies will advance our understanding of the kisspeptin/KISS1R system in the regulation of GnRH neuronal function at the time of puberty as well as during subsequent reproductive function and discover potential therapeutic targets for patients with reproductive disorders. Furthermore, completion of these studies will provide training in the generation of genetically manipulated mouse models and will enrich the Candidate's research experience in experimental design, aiding in the development of a successful independent translational investigator.

描述（由申请人提供）：青春期促性腺激素释放激素 (GnRH) 神经元的激活尚不清楚，但最近的证据表明 Kisspeptin-KISS1R 系统作为生殖发育和功能的关键调节剂的作用。虽然很明显 Kisspeptin 和 KISS1R 是神经内分泌级联的重要调节剂，但这种新型配体-受体系统在青春期以及随后的生殖功能期间 GnRH 神经元功能调节中的作用仍然存在许多问题。该项目的总体假设是 Kisspeptin 的细胞内信号转导受到 KISS1R 脱敏、内化和回收/降解的影响，从而在控制青春期时间和维持周期性生殖功能方面发挥关键作用。该项目的另一个假设是，更好地了解突变影响 Kisspeptin-KISS1R 系统的机制将具有临床意义，可以深入了解相关表型的病理生理学，为开发新的诊断工具以及患者及其家庭成员的遗传咨询奠定基础，并确定新的治疗靶点。我们提出以下具体目标：（1）表征KISS1R介导的细胞内信号传导、运输、周转、脱敏和再敏化； (2) 鉴定调节KISS1R信号传导的细胞外辅助因子并研究其在调节Kisspeptin介导的KISS1R激活中的作用机制； (3) 生成并表征 KISS1R (R386P) 敲入小鼠作为模型，以更好地了解该突变与中枢性性早熟 (CPP) 相关的机制。拟议研究的成功完成将加深我们对 Kisspeptin/KISS1R 系统在青春期以及随后的生殖功能期间 GnRH 神经元功能调节的理解，并为生殖障碍患者发现潜在的治疗靶点。此外，这些研究的完成将为生成基因操纵小鼠模型提供培训，并将丰富候选人在实验设计方面的研究经验，有助于培养一名成功的独立转化研究者。