SELECTION OF THE DOMINANT FOLLICLE AND THE IGF SYSTEM

在哺乳动物卵巢生物学中，是什么调节了从群体中选择特定数量的卵泡进行排卵是最重要的未回答的问题之一。该建议的重点是胰岛素样生长因子（IGF）系统在选择卵泡优势和潜在排卵中的潜在作用。 牛是此类研究的理想模型，因为超声成像已经阐明了卵泡募集、选择和优势的规律，这些规律以可预测的间隔发生，并且可以通过实验进行操纵。 已知IGF与FSH协同促进卵泡生长和分化。 相反，IGF结合蛋白（IGFBPs）结合IGF并抑制其在卵泡内的作用。 IGFBP蛋白酶从其BP释放IGF并使其作用于滤泡细胞。 我们的初步数据表明，抑制IGFBPs是低于在主导地位比在下属卵泡和主导卵泡获得蛋白酶的至少一个IGFBPs（IGFBP-4）左右的时间卵泡选择的优势。 因此，该建议的总体假设是，卵巢IGF系统在牛的优势卵泡的选择中起着关键作用。 首先通过测定卵泡液中抑制性IGFBP（BP-4和BP-2）及其推定蛋白酶的相对水平以及卵泡选择之前、期间和之后获得的卵泡组织中IGFBP及其mRNA的相对水平来检验该假设（特定目的1和2）。 在特定目标3中，将使用产生共显性卵泡的实验模型进一步检测IGFBP及其蛋白酶的显性和特异性变化之间的假定关联。 由于认为卵泡发育的波动是由血浆FSH的小幅增加引发的，因此具体目标4是确定促性腺激素对卵泡选择期间特定时间从卵泡中分离并体外培养的卵泡膜和颗粒细胞分泌IGFBP和IGFBP蛋白酶活性的影响。具体目标5是通过确定特定IGFBPs是否抑制促性腺激素和/或IGF-I诱导的颗粒细胞和卵泡膜细胞体外类固醇分泌，建立IGFBPs及其蛋白酶变化与优势卵泡选择之间的因果关系。

What regulates the selection, from among a cohort, of a species-specific number of follicles for ovulation is one of the most important unanswered questions in mammalian ovarian biology. This proposal is focused on the potential role of the insulin-like growth factor (IGF) system in selection of follicles for dominance and potential ovulation. Cattle are an ideal model for such studies because ultrasound imaging has elucidated the regular patterns of follicular recruitment, selection, and dominance that occur at predictable intervals and can be manipulated experimentally. IGF is known to synergize with FSH to promote follicular growth and differentiation. In contrast, IGF binding proteins (IGFBPs) bind IGF and inhibit its actions within the follicle. IGFBP proteases release IGF from its BPs and allow it to act on follicular cells. Our preliminary data indicate that inhibitory IGFBPs are lower in dominant than in subordinate follicles and that dominant follicles acquire a protease for at least one of the IGFBPs (IGFBP-4) around the time of follicular selection for dominance. Therefore, the overall hypothesis of this proposal is that the ovarian IGF system plays a critical role in the selection of the dominant follicle in cattle. This hypothesis will be tested first by determining the relative levels of inhibitory IGFBPs (BP-4 and BP-2) and their putative proteases in follicular fluid and relative levels of IGFBPs and their mRNAs in follicular tissue from follicles obtained before, during and after follicular selection (Specific Aims 1 and 2). In Specific Aim 3 an experimental model for producing co-dominant follicles will be used to further test the postulated association between dominance and specific changes in IGFBPs and their proteases. Since waves of follicular development are believed to be initiated by small increases in plasma FSH, Specific Aim 4 is to determine the effects of gonadotropins on the secretion of IGFBPs and IGFBP protease activity by theca and granulosa cells isolated from follicles at specific times during follicular selection and cultured in vitro. Specific Aim 5 is to establish a causal link between changes in IGFBPs and their proteases and selection of the dominant follicle by determining if specific IGFBPs inhibit gonadotropin and/or IGF-I-induced steroid secretion by granulosa and theca cells in vitro.