GPR30 Mediated-Estrogen Action on Ovarian Physiology and Ovarian Cancer

项目摘要 哺乳动物的卵巢不仅为生殖提供卵子，而且还提供雌性激素， 维持正常的生理机能然而，卵巢中的许多病理状况导致 女性不孕症和卵巢癌等疾病。我的长期目标是找出 分子，有助于卵巢的生理和病理变化， 可以开发新的诊断或治疗方法来改善妇女的 健康雌激素（E2）在卵巢的生理和病理中起着重要作用， 其机制尚不清楚。GPR 30被认为是一种膜雌激素 受体（mER）在许多细胞和组织中。我们已经证明GPR 30在 仓鼠卵巢和功能作为一个膜雌激素受体（mER），以调节 卵泡的形成和发育。然而， GPR 30介导的雌激素对卵泡发育的调节作用尚不清楚。同样地， GPR 30是否在卵巢癌发生中起作用同样不清楚。我假设 雌激素通过GPR 30调节卵巢细胞增殖、分化 在生理（卵泡形成的调节和 发展）和病理学（卵巢癌发生）状况。这项建议 将集中在GPR 30介导的雌激素作用的调节机制， 原始卵泡形成（K99期），以及GPR 30在卵巢癌中的作用 进展（R 00期）。具体目的是：1）检测GPR 30介导的E2 对卵巢细胞增殖、分化、通讯和存活的作用 在原始卵泡形成过程中，2）检查信号机制， GPR 30在卵巢体细胞中介导E2的作用，以及3）确定GPR 30的表达 GPR 30在卵巢癌组织中的表达及GPR 30在卵巢癌细胞增殖、侵袭和转移中的作用 和卵巢癌细胞的转移。K99/R 00计划的实现将使 卵巢细胞生理病理调节机制的探讨 GPR 30的功能，为药物发现和药物开发提供了有价值的信息。 开发用于与雌激素有关的生殖疾病的改进疗法， 卵巢早衰（POF）和卵巢癌，并促进我的职业生涯过渡 从博士后实习生到独立调查员

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.