Characterization of KISS1R, a G protein Coupled Receptor in Reproduction

生殖中 G 蛋白偶联受体 KISS1R 的表征

• 批准号: 8448075
• 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
• 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/8448075
• 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; 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; kisspeptin; loss of function mutation; mouse model; new therapeutic target; novel; novel diagnostics; receptor; reproductive; reproductive development; reproductive function; response; small molecule; therapeutic target; tool; trafficking

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系统是生殖发育和功能的关键调节剂。虽然很明显，Kisspeptin和kiss1r充当神经内分泌级联反应的基本调节剂，但有关这种新型配体 - 受体系统在青春期和随后的生殖功能期间，这种新型配体受体系统在调节GnRH神经元功能中的作用的许多问题仍然存在。该项目的基本假设是，基接吻蛋白的细胞内信号转导受到KISS1R的脱敏，内在化和回收/退化的影响，从而在控制青春期的时间和维持周期生殖功能方面起着关键作用。该项目的另一个假设是，对突变影响Kisspeptin-Kiss1R系统的机制有了更好的理解，将通过提供对相关表型的病理生理学的见解，从而具有临床意义，从而为开发新的诊断工具以及针对患者及其家人及其家人及其家庭成员的基因咨询而开发的基础，并确定了新的诊断目标。我们提出以下特定目的：（1）表征Kiss1r介导的细胞内信号传导，运输，周转，脱敏和敏感性； （2）确定调节KISS1R信号传导的细胞外辅助因素，并研究其在调节Kisspeptin介导的KISS1R激活中的作用机理； （3）生成和表征Kiss1r（R386p）敲入小鼠作为模型，以更好地了解该突变与中央早熟青春期（CPP）相关的机制。在青春期和随后的生殖功能期间，在调节GNRH神经元功能方面，成功完成了拟议的研究的成功完成将提高我们对Kisspeptin/kiss1r系统的理解，并发现生殖疾病患者的潜在治疗靶标。此外，这些研究的完成将为遗传操纵的小鼠模型的产生提供培训，并将丰富候选人在实验设计方面的研究经验，从而有助于开发成功的独立翻译研究者。