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

根据美国人口普查局的数据，65岁或以上的美国人将超过71岁。 到2030年，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。虽然在发展方面取得了很大进展， 干预措施，包括药物，以预防或治疗这些疾病，开发新的治疗方法， 减轻骨质流失和代谢功能障碍的策略可能会对儿童的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 代谢功能是促卵泡激素（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， 垂体前叶中的促性腺激素细胞，并作用于卵巢中的支持细胞以调节卵泡发生。 FSH对其他组织也有影响，了解其背后的确切生理机制， 这种激素的性腺外功能对于开发最有效的策略至关重要， 这个信号通路的临床应用。受FSH影响的性腺外组织包括骨， 脂肪组织Mone Zaidi和Clifford罗森实验室的精液研究表明， 在小鼠中抑制FSH信号传导可导致骨量增加、肥胖减少、 白色脂肪细胞和增加的能量消耗。基于FSH受体（FSHR）是 由破骨细胞和脂肪细胞表达，这两种细胞类型在体外对FSH有反应， 阻断FSH的这些性腺外效应被认为是由于FSH信号的丧失直接导致的， 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， 证明FSH在体内直接调节这些细胞类型的确定性研究尚未报道。 在这里，我们将采取遗传方法来阐明性腺外的生理机制， FSH的功能，特别是对骨骼和脂肪组织。我们要解决的总体问题是 FSH对这些组织的作用是否是通过直接向这些组织发出信号来介导的， 信号传导到其他组织的继发效应。我们的一般方法是使用一个敲入鼠标线， 我们已经产生了携带条件性Fshr flox等位基因，以靶向特定细胞类型中的FSH信号传导。 本项目的具体目的是确定靶向Fshr（1）在脂肪细胞中的作用，（2）在 破骨细胞，和（3）在体内的区域限制的方式。综上所述，我们认为， 这些研究将为性腺外调节的生理机制提供关键的见解， 组织FSH。我们相信这些研究是重要的，因为这些发现将有可能 对开发FSH调节信号传导策略的影响， 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。

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.