Elucidating extragonadal functions of follicle stimulating hormone using genetic approaches in mice

利用小鼠遗传方法阐明促卵泡激素的性腺外功能

• 批准号: 10685473
• 负责人: EMILY L GERMAIN-LEE
• 金额: $ 21.79万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10685473
• 关键词: Address; Adipocytes; Adipose tissue; Affect; Age; American; Anterior Pituitary Gland; Bone Density; Bone Tissue; Bone structure; Censuses; Clinical; Development; Elderly; Energy Metabolism; Fatty acid glycerol esters; Follicle Stimulating Hormone; Follicle Stimulating Hormone Receptor; G-Protein-Coupled Receptors; Goals; Health; Homeostasis; Hormone use; Hormones; In Vitro; Individual; Intervention; Knock-in Mouse; Laboratory Study; LoxP-flanked allele; Mediating; Metabolic; Metabolic Diseases; Metabolic dysfunction; Mus; Obesity; Osteoclasts; Osteoporosis; Ovarian; Ovary; Perimenopause; Persons; Pharmaceutical Preparations; Physiological; Pituitary Gland; Population; Regulation; Reporting; Role; Seminal; Signal Pathway; Signal Transduction; Signaling Molecule; Supporting Cell; Tissues; aged; bone; bone loss; bone mass; cell type; clinical application; folliculogenesis; genetic approach; gonad function; hormonal signals; in vivo; insight; novel therapeutic intervention; prevent; reproductive axis; reproductive hormone

According to the U.S. Census Bureau, the number of Americans aged 65 or older will rise to over 71 million by the year 2030. Among the major health challenges faced by individuals as they age are osteoporosis, obesity, and metabolic diseases. Although considerable progress has been made in developing interventions, including drugs, to prevent or treat these conditions, the development of new therapeutic strategies to mitigate bone loss and metabolic dysfunction could have a major impact on the overall health of our elderly population. One signaling molecule that has an important role in regulating both bone density and metabolic function is follicle stimulating hormone (FSH), which is a key component of the ovarian-pituitary reproductive axis. FSH, which is a hormone that signals through a G protein-coupled receptor, is made by gonadotrophs in the anterior pituitary gland and acts on support cells in the ovary to regulate folliculogenesis. FSH has effects on other tissues as well, and understanding the precise physiological mechanisms underlying the extragonadal functions of this hormone will be critical for developing the most effective strategies to target this signaling pathway for clinical applications. Among the extragonadal tissues affected by FSH are bone and adipose tissue. Seminal studies from the laboratories of Mone Zaidi and Clifford Rosen showed that systemic inhibition of FSH signaling in mice can cause increases in bone mass, reduced adiposity, increased beiging of white adipocytes, and increased energy expenditure. Based on the findings that the FSH receptor (FSHR) is expressed by osteoclasts and by adipocytes and that both of these cell types are responsive to FSH in vitro, these extragonadal effects of blocking FSH have been proposed to result from loss of FSH signaling directly to these tissues. Although these findings are consistent with a direct role for FSH signaling in these tissues, definitive studies demonstrating that FSH directly regulates these cell types in vivo have not yet been reported. Here, we will take a genetic approach to elucidate the physiological mechanisms underlying the extragonadal functions of FSH, specifically on bone and adipose tissue. The overall question that we will be addressing is whether effects of FSH on these tissues are mediated by direct signaling to those tissues or whether these are secondary effects of signaling to other tissues. Our general approach will be to use a knock-in mouse line that we have generated carrying a conditional Fshr flox allele in order to target FSH signaling in specific cell types. The Specific Aims of this project are to determine the effects of targeting Fshr (1) in adipocytes, (2) in osteoclasts, and (3) in a regionally-restricted manner in the body. Taken together, we believe that these studies will provide key insights into the physiological mechanisms underlying the regulation of extragonadal tissues by FSH. We believe that these studies are significant in that the findings will potentially have implications for the development of strategies to modulate signaling by FSH for a wide range of clinical applications characterized by metabolic dysfunction and bone loss, especially in the elderly.

根据美国人口普查局的数据，65岁或以上的美国人人数将超过71 到2030年，百万。随着年龄的年龄，个人面临的主要健康挑战 骨质疏松症，肥胖和代谢疾病。虽然在发展方面取得了很大进展 包括药物在内的干预措施，以防止或治疗这些疾病，开发新的治疗性 减轻骨质流失和代谢功能障碍的策略可能会对整体健康产生重大影响 我们的老年人。一个信号分子在调节骨密度和 代谢功能是卵泡刺激激素（FSH），这是卵巢 - 垂体的关键组成部分 生殖轴。 FSH是一种通过G蛋白偶联受体发出信号的激素，由 垂体前腺体中的促性腺营养物，并作用于卵巢中的支撑细胞，以调节卵泡发生。 FSH也对其他组织也有影响，并了解基础的精确生理机制 这种激素的外部功能对于制定针对目标的最有效策略至关重要 该临床应用的信号通路。在受FSH影响的外导期组织中，是骨头和 脂肪组织。 Mone Zaidi和Clifford Rosen实验室的开创性研究表明，系统性 小鼠中FSH信号传导的抑制会导致骨骼质量增加，肥胖降低，增加的糖尿病 白色脂肪细胞和能量消耗增加。基于FSH受体（FSHR）为 由破骨细胞和脂肪细胞表达，这两种细胞类型都对FSH的体外反应， 已提出了阻断FSH的这些外部效应是由于FSH信号的损失直接导致 这些组织。尽管这些发现与这些组织中FSH信号的直接作用一致，但 确切的研究表明，FSH直接调节体内这些细胞类型。 在这里，我们将采用一种遗传学方法来阐明术交性的生理机制 FSH的功能，特别是在骨骼和脂肪组织上。我们将要解决的总体问题是 FSH对这些组织的影响是否是通过直接信号传导向这些组织介导的，或者它们是否是 信号传导对其他组织的次要影响。我们的一般方法是使用一条敲击鼠标线 我们已经生成了有条件的FSHR Flox等位基因，以靶向特定细胞类型的FSH信号。 该项目的具体目的是确定靶向FSHR（1）在脂肪细胞中的影响，（2） 破骨细胞，（3）以区域限制的方式在体内。总之，我们相信这些 研究将为调节外部调节的生理机制提供关键的见解 FSH的组织。我们认为这些研究很重要，因为这些发现可能会有 对制定策略来调节FSH信号传导的影响 以代谢功能障碍和骨质流失为特征的应用，尤其是在老年人中。