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.

据美国人口普查局称，65岁或以上的美国人人数将增至71人以上 到 2030 年，人口将达到 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、肥胖症和代谢性疾病。尽管在开发方面已经取得了相当大的进展 预防或治疗这些疾病的干预措施（包括药物）、新疗法的开发 减轻骨质流失和代谢功能障碍的策略可能对整体健康产生重大影响 我们的老年人口。一种信号分子，在调节骨密度和骨密度方面具有重要作用 代谢功能是卵泡刺激素（FSH），它是卵巢-垂体的关键成分 生殖轴。 FSH 是一种通过 G 蛋白偶联受体发出信号的激素，由 垂体前叶中的促性腺激素作用于卵巢中的支持细胞以调节卵泡发生。 FSH 也对其他组织有影响，并了解其背后的精确生理机制 这种激素的性腺外功能对于制定最有效的策略至关重要 该信号通路的临床应用。受 FSH 影响的性腺外组织包括骨和 脂肪组织。 Mone Zaidi 和 Clifford Rosen 实验室的开创性研究表明，系统性 抑制小鼠 FSH 信号传导可导致骨量增加、肥胖减少、肤色增加 白色脂肪细胞，并增加能量消耗。基于 FSH 受体 (FSHR) 的研究结果 由破骨细胞和脂肪细胞表达，并且这两种细胞类型在体外对 FSH 有反应， 这些阻断 FSH 的性腺外效应被认为是由于 FSH 信号直接丧失所致。 这些组织。尽管这些发现与 FSH 信号在这些组织中的直接作用一致， 尚未有明确的研究表明 FSH 在体内直接调节这些细胞类型。 在这里，我们将采用遗传学方法来阐明性腺外的生理机制 FSH 的功能，特别是对骨和脂肪组织的功能。我们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向这些组织发出信号介导的，或者这些是否是 向其他组织发出信号的继发效应。我们的一般方法是使用敲入小鼠系 我们已经生成了携带条件性 Fshr flox 等位基因的基因，以便针对特定细胞类型中的 FSH 信号传导。 该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）在体内以区域限制的方式。综合起来，我们认为这些 研究将为性腺外调节的生理机制提供重要见解 FSH 组织。我们相信这些研究具有重要意义，因为研究结果可能会产生影响 对制定通过 FSH 调节信号传导的策略对广泛的临床的影响 以代谢功能障碍和骨质流失为特征的应用，尤其是老年人。