GPR30 Mediated-Estrogen Action on Ovarian Physiology and Ovarian Cancer

GPR30 介导的雌激素对卵巢生理和卵巢癌的作用

• 批准号: 8546439
• 负责人: Cheng Wang
• 金额: $ 23.09万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-17 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8546439
• 关键词: 1-Phosphatidylinositol 3-Kinase; Achievement; Address; Agonist; Antiestrogen Therapy; Apoptosis; Appearance; Aromatase; Binding; Biochemistry; Biological Assay; Biological Models; Biology; Calcium; Cancer Patient; Cancer cell line; Cell Communication; Cell Proliferation; Cell physiology; Cells; Communication; Data; Development; Diagnosis; Disease; Electronics; Endometrial Carcinoma; Endometrial Neoplasms; Epithelial Cells; Estradiol; Estrogen Receptors; Estrogen Therapy; Estrogens; Female; Female infertility; Gene Expression; Gene Targeting; Genetic Recombination; Germ Cells; Goals; Hamsters; Hormones; Human; ICI 182780; Image; In Vitro; Infertility; Knockout Mice; Knowledge; Light; Link; MLLT7 gene; Malignant neoplasm of ovary; Mammary Neoplasms; Mediating; Membrane; Mentors; Methods; Microscopy; Modeling; Neonatal; Neoplasm Metastasis; Nuclear; Ovarian; Ovary; Pathology; Pathway interactions; Phase; Physiological; Physiology; Play; Primordial Follicle; Recombinants; Regulation; Reporting; Reproduction; Research; Research Personnel; Role; Signal Transduction; Signaling Molecule; Small Interfering RNA; Somatic Cell; Surface; Survival Rate; Techniques; Tissue Microarray; Tissue Recombination; Tissues; Women' s Health; cDNA Arrays; cancer cell; carcinogenesis; career; cell type; cohort; design; drug discovery; egg; estradiol-bovine serum albumin; folliculogenesis; improved; in vivo; inhibitor/antagonist; insight; malignant breast neoplasm; novel; novel diagnostics; novel therapeutics; ovarian neoplasm; overexpression; postnatal; premature; programs; public health relevance; receptor; reproductive; response; stem; tool; transmission process; tumor progression; wortmannin

Project summary Mammalian ovary provides not only eggs for reproduction, but also female hormones to maintain normal physiology. However, many pathological conditions in the ovary result in female infertility and diseases such as ovarian cancer. My long-term goal is to identify molecules that contribute to the physiological and pathological changes in the ovary so that novel diagnostic or therapeutic methods can be developed for improving women's health. Estrogen (E2) plays an important role in ovarian physiology and pathology, but the mechanisms are still unclear. GPR30 has been implied as a membrane estrogen receptor (mER) in many cells and tissues. we have shown that GPR30 is expressed in the hamster ovary and functions as a membrane estrogen receptor (mER) to regualte ovarain follicle formation and development. However, the mechanism underlying GPR30-mediated estrogen regualtion of follicle development is still unknown. Similarly, whether GPR30 plays a role in ovarain carcinogenesis is equally unclear. I hypothesize that estrogen, acting via GPR30, regualtes ovarian cell proliferation, differentiation and survival under both physiological (regualtion of follicle formation and development) and pathological (ovarian carcinogenesis) conditions. This proposal will focus on the mechanisms of GPR30-mediated estrogen action on the regulation of primordial follicle formation (K99 phase), and on the function of GPR30 in ovarian cancer progression (R00 phase). The specific aims are: 1) to examine the GPR30-mediated E2 action on the proliferation, differentiation, communication and survival of ovarian cells during primordial follicle formation, 2) to examine the signaling mechanisms whereby GPR30 mediates E2 action in ovarian somatic cells, and 3) to determine the expression of GPR30 in ovarian cancer tissues and the function of GPR30 in the proliferation, invasion and metastasis of ovarian cancer cells. Achievement of this k99/R00 program will shed light on the mechanism of physiological and pathological regualtion of ovarian cell functions by GPR30, provide valuable information for drug discovery and the development of improved therapy for estrogen-related reproductive diseases such as premature ovarian faliure (POF) and ovarian cancer, and facilitate transition of my career from a postdoctoral trainee to independent investigator.

项目摘要 哺乳动物卵巢不仅提供卵子的卵，而且还提供女性激素 保持正常生理。但是，卵巢中的许多病理状况导致 女性不育症和卵巢癌等疾病。我的长期目标是确定 有助于卵巢的生理和病理变化的分子 可以开发出新的诊断或治疗方法来改善妇女 健康。雌激素（E2）在卵巢生理和病理学中起重要作用，但 这些机制仍不清楚。 GPR30已暗示为膜雌激素 许多细胞和组织中的受体（MER）。我们已经证明了GPR30在 仓鼠卵巢和作为膜雌激素受体（MER）的作用 卵球蛋白卵泡形成和发育。但是，基础机制 GPR30介导的卵泡发育的雌激素恢复仍然未知。相似地， GPR30是否在卵巢致癌作用中起作用。我假设 通过GPR30起作用的雌激素会导致卵巢细胞增殖，分化 和生存下的生存（卵泡形成的恢复和 发育）和病理（卵巢致癌）条件。这个建议 将侧重于GPR30介导的雌激素作用对调节的机制 原始卵泡形成（K99期），以及GPR30在卵巢癌中的功能 进展（R00相）。具体目的是：1）检查GPR30介导的E2 对卵巢细胞的增殖，分化，交流和存活的作用 在原始卵泡形成期间，2）检查信号传导机制 GPR30介导卵巢体细胞中的E2作用，3）确定表达 卵巢癌组织中的GPR30和GPR30在增殖中的功能 和卵巢癌细胞的转移。这个K99/R00计划的实现将丢弃 关于卵巢细胞的生理和病理恢复机制的光 GPR30的功能，为药物发现提供了有价值的信息和 开发改进的雌激素相关生殖疾病的治疗 早产卵巢恶魔（POF）和卵巢癌，并促进我的职业过渡 从博士后实习生到独立调查员。