HORMONE MEDIATED REGULATION OF OVARIAN FUNCTION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 这个项目探索雌激素对卵巢和乳腺的作用。在过去的资助期间进行的研究探索了1)卵巢基质金属蛋白酶，2)卵巢基因表达，3)一类核激素受体，即过氧化物酶体增殖物激活受体(PPAR)在乳腺功能中的变化。与该项目有关的所有四名调查人员在各自的实验以及为该项目的竞争性更新建立初步数据方面都取得了重大进展。Jo Misung博士正在继续研究一种名为RUNX1的新基因在卵泡发育后期的功能意义。RUNX1表达的定位模式和RUNX1表达的机制(S)继续阐明该蛋白在卵泡发育和排卵中所起的功能作用。沉默RNA的初步实验表明，RUNX1可能介导了黄体生成素诱导的孕酮产生的增加。Michael Kilgore博士的实验继续研究雌激素受体β(Erb)和过氧化物酶体增殖物激活受体γ(PPARg)之间的信号串扰。初步数据表明，这些受体之间的串扰导致了基因特异性的变化，如DNA微阵列所见，一些基因上调，而其他基因下调。正在进行的研究正在研究这些基因表达变化对细胞增殖和迁移的意义。最后，Jay Ko博士的一系列育种实验正在进行中，以产生组织特异性的雌激素受体(ER)亚型的敲除。这些正在进行的研究正在创造在卵母细胞、颗粒细胞或卵泡膜细胞中缺乏ERB或ERB的小鼠。到目前为止，已经产生了缺乏ERA的卵母细胞特异性雌激素受体基因敲除。这些小鼠虽然有生育能力，但排卵能力降低。随着这些小鼠的出现，将探索雌激素对卵泡膜和颗粒细胞层的影响。在库里博士的实验室里，基质金属蛋白酶-19及其抑制物在卵巢发育和排卵中的作用和表达的时间仍未揭开。这些研究证明了组织重塑在调节卵巢功能和生育能力方面的重要性。因此，所有项目在开发必要的工具以实现每个项目的目标方面都取得了重大进展，并处于有利地位，能够为科布雷项目的竞争性更新提供令人信服的数据，并争取外部支持。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project explores estrogen action on the ovary and the mammary gland. Studies conducted during the past funding period have explored the changes in 1) the ovarian matrix metalloproteinases, 2) ovarian gene expression, and 3) a class of nuclear hormone receptors, the peroxisome proliferator-activated receptors (PPARs), in mammary gland function. All four of the investigators associated with this project have made significant progress towards their individual experiments as well as towards establishing preliminary data for the competitive renewal of this Project. Dr. Misung Jo is continuing to examine the functional significance of a novel gene, Runx1, in late follicle development. The localization pattern of Runx1 expression and the mechanism(s) of Runx1 expression continue to shed light on the functional role this protein plays in follicular development and ovulation. Preliminary experiments with silencing RNA have suggested that Runx1 may mediate the LH induced increase in progesterone production. Experiments by Dr. Michael Kilgore have continued to investigate the signal crosstalk between the estrogen receptor beta (ERb) and the peroxisome proliferator-activated receptor gamma (PPARg). Preliminary data indicates that crosstalk between these receptors results in gene-specific changes with a number of genes being upregulated while other genes are downregulated as seen by DNA microarray. Ongoing studies are examining the significance of these changes in gene expression on cellular proliferation and migration. Finally, a series of breeding experiments by Dr. Jay Ko have been in progress to generate tissue-specific knockouts of the estrogen receptor (ER) isoforms. These ongoing studies are creating mice which lack ERa or ERb in the oocyte, the granulosa cell, or the theca cells. To date, oocyte-specific estrogen receptor knockout have been generated which lack ERa. These mice exhibit a reduced ovulatory capacity although they are fertile. The impact of estrogen action on the theca and granulosa cell layers of the follicle will be explored as these mice become available. In Dr. Curry's laboratory, the role and timing of expression of the matrix metalloproteinase-19 and its inhibitors in ovarian development and ovulation continues to be unraveled. These studies demonstrate the importance of tissue remodeling in regulating ovarian function and fertility. Therefore, all the projects have made significant progress in developing the necessary tools to address the goals of each project and are in an excellent position to provide convincing data for the competitive renewal of the COBRE project as well as compete for extramural support.