GREB1 Action in Endometrial Function and Dysfunction

GREB1 在子宫内膜功能和功能障碍中的作用

• 批准号: 9049524
• 负责人: Ramakrishna Kommagani
• 金额: $ 11.07万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-15 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9049524
• 关键词: Address; Advanced Development; Androgens; Biochemical; Cell physiology; Cells; Clinical; Clinical Management; Decidual Cell; Decidual Cell Reactions; Diagnosis; Diagnostic; Embryo; Endometrial; Endometrial Disorder; Endometrial Stromal Cell; Endometriomas; Endometrium; Engineering; Estrogens; Failure; Female infertility; Foundations; Functional disorder; Future; Genes; Genetic Transcription; Genomic approach; Gonadal Steroid Hormones; Growth; Health; Human; Infertility; Knowledge; Lead; Link; Mediating; Mentors; Modeling; Molecular; Molecular Target; Mus; Natural regeneration; Nuclear Receptors; Outcome; Pathogenesis; Pathology; Patients; Phase; Physiology; Process; Progesterone; Progesterone Receptors; Regulation; Reporting; Reproductive Health; Role; Science; Signal Pathway; Spontaneous abortion; Staging; Stromal Cells; Tissues; Training; Transcriptional Regulation; Uterus; Woman; Work; Xenograft procedure; base; blastocyst; career; career development; endometriosis; failure Implantation; functional genomics; genome-wide analysis; implantation; in vivo; innovation; insight; malignant breast neoplasm; mouse model; natural Blastocyst Implantation; overexpression; programs; prostate cancer cell; reconstitution; reproductive; response; steroid hormone; translational study

 DESCRIPTION (provided by applicant): Even when the blastocyst develops normally, inadequate differentiation of stromal cells to decidual cells in the endometrium (termed decidualization) can lead to implantation failure or early embryo miscarriage. Although many of the cellular mechanisms that underpin steroid-hormone actions in endometrial physiology are well defined, a significant knowledge-gap exists concerning the coregulator and signaling pathways that control or mediate steroid-hormone responses in the decidualization process. This knowledge-gap is significant as without new mechanistic insights into this aspect of embryo implantation, the ability to diagnose and/or treat infertility based on a functionally impaired endometrium will not be realized. Recently, I identified GREB1 as a progesterone responsive gene and critical for the induction of progesterone molecular targets required for decidualization of primary human endometrial stromal cells in culture. Therefore, this finding implicates a coactivator role for GREB1 in this cellular process. In parallel studies, I also showed that GREB1 is required for estrogen-driven proliferation of endometrioma cells derived from endometriosis patients, indicating a separate role for GREB1 in estrogen-dependent endometriosis. Based on my preliminary observations, I hypothesize that the coactivator function of GREB1 is required both for progesterone-driven endometrial decidualization and for estrogen-dependent endometriosis progression. Therefore, my proposal plans to examine the dual role of GREB1 in endometrial function and dysfunction. The K99 phase will establish the in vivo role of GREB1 in normal endometrial responses to progesterone exposure using a recently engineered mouse model. These studies will transition into the R00 portion, which uses this model to define the pathogenic importance of GREB1 in estrogen-driven endometriosis. The R00 phase will also determine the molecular mechanism that underpins the coactivator function of GREB1 in progesterone-driven human endometrial decidualization. Combined with career development training, which will include mentoring, course work, and presentation opportunities, these studies will extend my training in endometrial physiology and pathophysiology to provide a strong foundation to launch an independent career in the reproductive sciences in near future.

 描述(申请人提供)：即使在胚泡发育正常的情况下，子宫内膜的间质细胞和蜕膜细胞分化不充分(称为蜕膜化)也可能导致着床失败或早期胚胎流产。尽管在子宫内膜生理学中支持类固醇激素作用的许多细胞机制已经明确，但关于在蜕膜形成过程中控制或介导类固醇激素反应的辅助调节因子和信号通路，仍存在着显著的知识差距。这一知识差距是显著的，因为如果没有对胚胎植入这一方面的新的机械性见解，诊断和/或治疗基于功能受损的子宫内膜的不孕症的能力将无法实现。最近，我发现GREB1是一种孕酮反应基因，对原代培养的人子宫内膜间质细胞蜕膜形成所需的孕酮分子靶点的诱导至关重要。因此，这一发现暗示了GREB1在这一细胞过程中的协同激活作用。在平行研究中，我还表明GREB1是雌激素驱动的子宫内膜异位症患者子宫内膜瘤细胞增殖所必需的，这表明GREB1在雌激素依赖的子宫内膜异位症中起着单独的作用。根据我的初步观察，我假设GREB1的辅助激活功能对于孕激素驱动的子宫内膜蜕膜化和雌激素依赖型子宫内膜异位症的进展都是必需的。因此，我的提案计划研究GREB1在子宫内膜功能和功能障碍中的双重作用。K99期将利用最近设计的小鼠模型建立GREB1在正常子宫内膜对孕激素暴露的反应中的体内作用。这些研究将过渡到R00部分，该部分使用这个模型来确定GREB1在雌激素驱动的子宫内膜异位症中的致病重要性。R00期也将决定GREB1在孕酮驱动的人子宫内膜蜕膜化中辅助激活功能的分子机制。结合职业发展培训，包括指导、课程工作和演讲机会，这些研究将扩展我在子宫内膜生理学和病理生理学方面的培训，为在不久的将来在生殖科学领域开始独立的职业生涯奠定坚实的基础。

项目成果

Application of 13C isotope labeling using liquid chromatography mass spectrometry (LC-MS) to determining phosphate-containing metabolic incorporation.

• DOI: 10.1002/jms.3292
• 发表时间: 2013
• 期刊: Journal of mass spectrometry : JMS
• 作者: S. K. Bhowmik;V. Putluri;R. Kommagani;S. A. Konde;J. Lydon;A. Sreekumar;N. Putluri