卵巢衰老是导致女性生殖障碍的重要因素，亦严重影响女性身心健康。关于卵巢功能不全病因及机制研究渐成热点，但女性年龄相关性卵巢功能衰退的研究甚少，其调控机制迄今不明。申请人前期已构建不同年龄段女性卵巢颗粒细胞mRNA表达谱，通过生物信息学分析及RT-PCR证实了FHL蛋白家族在高龄女性卵巢颗粒细胞中显著高表达。进一步扩大样本检测分析发现FHL2/FHL3 mRNA的转录水平随年龄增长呈线性变化，提示FHL蛋白家族在卵巢功能生理性衰退过程可能发挥重要作用；体外实验证实FSH可浓度依赖性地上调颗粒细胞中FHL2/3转录水平。本项目拟以FHL2/3蛋白为切入点，从分子、细胞、临床标本及动物模型多层次研究明确年龄相关的高FSH水平通过FHL2/3蛋白调控卵巢功能生理性衰退的效应及分子机制，初步阐明FHL2/3蛋白介导的卵巢功能生理性衰退的精细调控网络，为卵巢衰老的早期预测及干预提供潜在靶点。

Ovarian aging is one of the most important leading causes of female reproductive disorders, and seriously affects women's physical and mental health. The research on the etiology and pathogenesis of ovarian insufficiency has become a hot topic, but there are few studies on the age-related decline of ovarian function in women, and its regulation mechanism is still unknown. The applicants have successfully constructed mRNA expression profiles of ovarian granulosa cells of groups at different ages. We founded that FHL protein family was highly expressed in ovarian granulosa cells in older women by bioinformatics analysis and RT-PCR. Moreover, we found the linear changes between the mRNA level of FHL2/FHL3 protein and maternal age by expanding sample amount, further indicating that FHL protein family might play an important role in the physiological decline of ovarian function. In vitro experiments confirmed that FSH can up-regulate FHL2/3 in transcription levels in granulosa cells in a concentration-dependent manner. This project intends to use FHL2/3 protein as an entry point to study the effects and molecular mechanism of age-related high FSH levels regulating the physiological decline of ovarian function through FHL2/3 protein on molecular, cell, clinical specimens and animal models to elucidate the FHL2/3 protein-mediated fine-regulation network of the physiological decline of ovarian function, providing a potential target for early prediction and intervention of ovarian aging.