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PGRMC1 function in female reproductive physiology

PGRMC1 在女性生殖生理学中的功能

基本信息

批准号：
8011956
负责人：
JOHN J PELUSO
金额：
$ 26.26万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-15 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8011956
关键词：
Agonist Apoptosis Binding Binding Proteins Cell Differentiation process Cell Line Cell Survival Cells Cholesterol Data Decidual Cell Reactions Development Endometrial Endometrium Epithelial Cell Proliferation Estrogens Estrous Cycle Female Fertility Gene Expression Goals Gonadotropins Grant Granulosa-Lutein Cells Growth Histocompatibility Hormones Human Immune system Immunoprecipitation In Vitro Infertility Knockout Mice Lead Ligands Longevity Luteal Cells Malignant Neoplasms Malignant neoplasm of ovary Mediating Mediator of activation protein Membrane Mesenchymal Mitosis Monitor Mouse Strains Mus Mutation Nuclear Ovarian Ovary Ovulation Physiological Play Pregnancy Premature Ovarian Failure Progesterone Progesterone Receptors Protein Binding Proteomics Reproduction Reproductive Physiology Reproductive Process Research Personnel Role Site Staging Steroids Stromal Cells Technology Testing Tissues Two-Dimensional Gel Electrophoresis Uterine Cancer Uterus base embryo/fetus granulosa cell implantation in vivo natural Blastocyst Implantation public health relevance receptor reproductive reproductive axis reproductive function transcription factor

项目摘要

DESCRIPTION (provided by applicant): Progesterone (P4) is an essential hormone that regulates the entire reproductive process. P4 has many target sites throughout the reproductive axis but two major sites of action include the ovary and the uterus. The ovary synthesizes and secretes P4 throughout the menstrual/estrous cycle with its levels increasing during pregnancy. P4 acts directly of the granulosa cells of the ovary to inhibit mitosis and apoptosis. In addition, the P4 promotes the viability and steroidogenic potential of luteal cells and stimulates both its own secretion and cholesterol synthesis. Many of the actions of P4 within the ovary and uterus are mediated by classical nuclear P4 receptors (PGRs). However, not all of the actions of P4 can be explained by activation of PGRs, since a number of cell lines that do not express these receptors, as well as Pgr null mice, are able to respond to P4. Our recent in vitro studies of ovarian and uterine cells have revealed that some actions of P4 such as granulosa/luteal cell viability, P4 synthesis and uterine stromal cell differentiation are mediated in part through the P4 binding protein, Progesterone Receptor Membrane Component-1 (PGRMC1). Based on these in vitro data, we hypothesize that PGRMC1 plays essential roles in regulating ovarian and uterine function in vivo. In this grant we will directly test our hypothesis by generating a conditional knockout mouse in which PGRMC1 is specifically depleted within the granulosa/luteal cells of the ovary and the mesenchymal (stromal) tissue of the uterus (Specific Aim 1). We will then use the conditional PGRMC1 knockout mouse to monitor the effects of depleting PGRMC1 on 1) female fertility, 2) ovarian function (i.e. follicular growth, steroid synthesis and ovulation) and 3) uterine function (i.e. endometrial decidualization and embryo implantation) (Specific Aim 2). In Specific Aim 3 we will isolate PGRMC1 binding proteins by immunoprecipitation using lysates of ovarian and uterine tissues and then using two- dimensional gel electrophoresis and subsequent proteomics to identify PGRMC1 binding partners. The successful completion of the proposed studies will provide compelling evident to support PGRMC1's role in female reproductive physiology. What is important about establishing PGRMC1 as a mediator of specific ovarian and uterine functions is that this will allow for the development of a new class of P4 antagonists and agonists. These putative PGRMC1 modulators would be completely different from the present-day PGR antagonists and would only interfere with the actions of P4 that are mediated via PGRMC1 and not the PGR. These putative PGRMC1 modulators could find application in the treatment of human fertility and potentially ovarian cancers, since PGRMC1 promotes the viability of these cancers. PUBLIC HEALTH RELEVANCE: Progesterone (P4) is an essential hormone that regulates the entire female reproductive process. Our recent in vitro studies of ovarian and uterine cells have revealed that some actions of P4 such as granulosa/luteal cell viability, P4 synthesis and uterine stromal cell differentiation are mediated in part through the P4 binding protein, Progesterone Receptor Membrane Component-1 (PGRMC1). In this grant we will conclusively determine the role of PGRMC1 by generating a conditional knockout mouse and then monitoring the effects of depleting PGRMC1 on 1) female fertility, 2) ovarian function and 3) uterine function. If successful, the proposed studies could lead to the development of a new class of P4 antagonists and agonists that could be used to treat human infertility and potentially ovarian and uterine cancers.

描述（由申请人提供）：孕酮（P4）是一种调节整个生殖过程的必需激素。P4在整个生殖轴上有许多靶点，但两个主要的作用部位包括卵巢和子宫。卵巢在整个月经/发情周期中合成和分泌P4，其水平在怀孕期间增加。P4直接作用于卵巢颗粒细胞，抑制有丝分裂和凋亡。此外，P4促进黄体细胞的活力和类固醇生成潜力，并刺激其自身的分泌和胆固醇合成。P4在卵巢和子宫内的许多作用是由经典的核P4受体（PGR）介导的。然而，并非P4的所有作用都可以通过PGR的激活来解释，因为许多不表达这些受体的细胞系以及Pgr缺失小鼠能够对P4产生应答。我们最近对卵巢和子宫细胞的体外研究表明，P4的一些作用，如颗粒/黄体细胞活力，P4合成和子宫基质细胞分化，部分是通过P4结合蛋白，孕酮受体膜成分1（PGRMC 1）介导的。基于这些体外数据，我们假设PGRMC 1在体内调节卵巢和子宫功能中起重要作用。在这项研究中，我们将通过产生一种条件性敲除小鼠来直接测试我们的假设，在这种小鼠中，PGRMC 1在卵巢的颗粒细胞/黄体细胞和子宫的间充质（基质）组织中特异性耗尽（特异性目的1）。然后，我们将使用条件性PGRMC 1敲除小鼠监测消耗PGRMC 1对1）雌性生育力、2）卵巢功能（即卵泡生长、类固醇合成和排卵）和3）子宫功能（即子宫内膜蜕膜化和胚胎着床）的影响（具体目标2）。在具体目标3中，我们将使用卵巢和子宫组织的裂解物通过免疫沉淀分离PGRMC 1结合蛋白，然后使用二维凝胶电泳和随后的蛋白质组学来鉴定PGRMC 1结合伴侣。这些研究的成功完成将为支持PGRMC 1在女性生殖生理学中的作用提供令人信服的证据。将PGRMC 1确定为特异性卵巢和子宫功能的介体的重要性在于，这将允许开发一类新的P4拮抗剂和激动剂。这些推定的PGRMC 1调节剂将与目前的PGR拮抗剂完全不同，并且将仅干扰P4的作用，所述P4的作用是通过PGRMC 1而不是PGR介导的。这些推定的PGRMC 1调节剂可以应用于治疗人类生育和潜在的卵巢癌，因为PGRMC 1促进这些癌症的生存能力。孕激素（P4）是一种调节整个女性生殖过程的基本激素。我们最近对卵巢和子宫细胞的体外研究表明，P4的一些作用，如颗粒/黄体细胞活力，P4合成和子宫基质细胞分化，部分是通过P4结合蛋白，孕酮受体膜成分1（PGRMC 1）介导的。在这项研究中，我们将通过产生条件性敲除小鼠，然后监测消耗PGRMC 1对1）女性生育力，2）卵巢功能和3）子宫功能的影响，最终确定PGRMC 1的作用。如果成功，拟议的研究可能会导致一类新的P4拮抗剂和激动剂的开发，可用于治疗人类不育症和潜在的卵巢癌和子宫癌。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Progesterone receptor membrane component 1 deficiency attenuates growth while promoting chemosensitivity of human endometrial xenograft tumors.

DOI：
10.1016/j.canlet.2014.09.036
发表时间：
2015-01-28
期刊：
CANCER LETTERS
影响因子：
9.7
作者：
Friel, Anne M.;Zhang, Ling;Pru, Cindy A.;Clark, Nicole C.;McCallum, Melissa L.;Blok, Leen J.;Shioda, Toshi;Peluso, John J.;Rueda, Bo R.;Pru, James K.
通讯作者：
Pru, James K.

PGRMC1 and PGRMC2 in uterine physiology and disease.