卵泡微环境中胶原受体DDR2调控卵泡发育及排卵的作用与机制研究

卵泡发育及排卵障碍占女性不孕不育的1/4强，其原因非常复杂；近年，细胞外基质微环境在卵泡发育及排卵中的重要调控作用备受关注。据报道，胶原盘状结构域受体2(DDR2)在卵泡发育及排卵期显著增高，呈周期性变化，Ddr2-/-小鼠排卵障碍，且对促性腺激素不敏感，但详细作用机制尚不清楚。我们研究发现，DDR2高表达于卵泡膜细胞和增殖的颗粒细胞，而Ddr2-/-小鼠卵泡膜则变薄，LHR、雄、雌、孕激素等显著降低，提示LHR及性激素降低可能影响膜细胞分化成熟和颗粒细胞的功能，进而导致卵泡发育及排卵障碍。因此，本项目拟利用临床标本、Ddr2-/-小鼠、卵泡3D培养及分子生物学技术，研究基质胶原激活卵泡体细胞DDR2调控卵泡发育及排卵的作用与机制，重点关注DDR2调控LHR的产生机制，揭示卵巢内细胞外基质胶原及DDR2的新功能，为临床卵巢低反应性不孕症的诊断和治疗提供新思路和新靶点。

Follicular development and ovulation disorders account for excessively a quarter of female infertility, the reasons for which are sophisticated to account for. Recent years, the regulation of the micro-environment composed by extra-cellular matrix has been paid significant attention to follicular development and ovulation. It is covered that, as a fibrillar collagen receptor, Discoidin Domain Receptor 2 (DDR2), widely expressed in ovary interstitial, has a cyclic variation and becomes notably higher in the follicular development and ovulation. Ddr2-/- mice have ovulation obstacle and present outstandingly lower reactivity to gonadotropins, however, the mechanism is unknown. It is found in our study that DDR2 is highly expressed in theca cells and granulosa cells. The thecal of Ddr2-/- mice is thin with far lower LHR, androgen, estrogen and progesterone and the cell proliferation is inhibited, which hypothetically contribute to the follicular development and ovulation obstacle resulting from inhibition of the expression of LHR and both thecal differentiation and granular cell proliferation. Employing clinic samples, Ddr2-/- mice, and 3D culture of follicle as well as molecular biology technology, this project intends to research on the function and mechanism of collagen regulating theca cells and granular cells by DDR2 to affect follicular and ovulation, in particular, on the mechanism of DDR2 regulating LHR expression, and to reveal new function and mechanism of DDR2 and collagen in ovarian micro-environment, so as to supply reference to the diagnosis and treatment of infertility caused by poor ovarian Response.