颗粒细胞EHD1调节FSHR的循环转运影响FSH敏感性的机制研究

在行IVF周期的患者中，常出现患者FSH水平高，但是卵泡反应不敏感的现象。这可能与FSH的受体FSHR发生突变或在颗粒细胞中表达下调，导致FSH不能有效作用于卵泡有关。FSHR是FSH发挥作用的必经之路，细胞通过调控FSHR的内吞、循环转运过程调节其对FSH的敏感性。我们的前期研究发现，部分病人的FSHR表达正常，但是对FSH刺激不敏感，出现高FSH症状。进一步研究发现受体内吞循环转运调节分子EHD1在高FSH水平患者的颗粒细胞中显著降低，提示我们这一部分病人出现高FSH是由于FSHR内化后不能顺利循环转运至膜，颗粒细胞对FSH不敏感，导致FSH代偿性升高所致。本项目拟在前期工作基础上，从临床样本、动物模型和细胞水平等层面研究EHD1参与调节颗粒细胞FSHR的循环转运影响颗粒细胞增殖和窦状卵泡生长发育的机制。为了解卵泡发育的分子机制和解决高FSH患者的FSH敏感性提供实验证据和理论依据。

Some patients undergoing in vitro fertilization showed high levels of FSH but low follicular response. This may be related to the mutation of FSHR or the down-regulation of FSHR on the granulosa cell surface, resulting in the inability of FSH to effectively act on follicles. FSHR is the only way for FSH to play its work. Granulosa cells regulate their sensitivity to FSH by regulating the endocytosis and recycling of FSHR. Our previous study found that some patients had normal FSHR expression, but were not sensitive to FSH stimulation, and developed symptoms of high FSH. Further studies found that the receptor recycling regulator EHD1 was significantly reduced in granulosa cells of patients with high FSH levels, suggesting that in this part of patients, high FSH was caused by the fact that FSHR could not be effectively recycled to the cell membrane and granulosa cells were not sensitive to FSH, leading to compensatory increase of FSH. In the present study, we intend to investigate the molecular mechanism of EHD1 regulating the FSHR recycling process in granulosa cells by in vitro and in vivo experiments, and to elucidate the effect of this process on granulosa cell proliferation and antral follicular development. This study will provide new insights into the molecular mechanisms of follicular development and FSH sensitivity in patients with high FSH.