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岁或以上的美国人的数量将上升到71岁以上 到2030年达到100万。随着年龄的增长，个人面临的主要健康挑战包括 骨质疏松症、肥胖和代谢性疾病。尽管在发展方面取得了长足的进步 包括药物在内的干预措施，以预防或治疗这些疾病，开发新的治疗方法 缓解骨质流失和代谢功能障碍的策略可能会对 我们的老年人口。一种信号分子，在调节骨密度和 代谢功能是卵泡刺激素(FSH)，它是卵巢-垂体的关键组成部分 生殖轴。卵泡刺激素是一种通过G蛋白偶联受体传递信号的激素，由 促性腺激素位于脑下垂体前叶，作用于卵巢中的支持细胞来调节卵泡的发生。 卵泡刺激素对其他组织也有影响，并了解其确切的生理机制。 这种荷尔蒙的性腺外功能对于开发最有效的靶向策略至关重要。 这一信号通路在临床上的应用。在受FSH影响的性腺外组织中，骨和 脂肪组织。来自Mone Zaidi和Clifford Rosen实验室的开创性研究表明，系统性 抑制小鼠的FSH信号可以导致骨量增加，肥胖减少，皮肤发黑 白色脂肪细胞，增加能量消耗。基于FSH受体(FSHR)是 破骨细胞和脂肪细胞表达，这两种类型的细胞在体外对FSH都有反应， 这些阻断FSH的性腺外效应被认为是由于FSH信号的丢失直接导致的 这些纸巾。尽管这些发现与FSH信号在这些组织中的直接作用是一致的， 有关FSH在体内直接调节这些细胞类型的权威研究尚未见报道。 在这里，我们将用遗传学的方法来阐明性腺外的生理机制。 促卵泡激素的功能，特别是在骨骼和脂肪组织。我们将解决的总体问题是 促卵泡激素对这些组织的影响是通过直接信号传递给这些组织还是通过 对其他组织发出信号的次要影响。我们的一般方法将是使用敲入鼠标行 我们已经产生了携带条件FSHR FLOX等位基因，以便在特定细胞类型中靶向FSH信号。 这个项目的具体目标是确定靶向FSHR(1)在脂肪细胞中的效果，(2)在 破骨细胞，以及(3)在体内以区域受限的方式。总而言之，我们认为这些 研究将为性腺外激素调节的生理机制提供关键的见解。 组织用促卵泡刺激素。我们认为这些研究具有重要意义，因为这些发现可能会 FSH信号调控策略的发展对临床广泛应用的启示 以代谢功能障碍和骨质丢失为特征的应用，尤其是在老年人。