GPR30 Mediated-Estrogen Action on Ovarian Physiology and Ovarian Cancer

描述（申请人提供）：哺乳动物卵巢不仅提供生殖所需的卵子，还提供维持正常生理的雌性激素。然而，卵巢的许多病理状况导致女性不育和卵巢癌等疾病。我的长期目标是确定导致卵巢生理和病理变化的分子，从而开发出新的诊断或治疗方法，以改善女性的健康。雌激素（E2）在卵巢生理病理中起重要作用，但其机制尚不清楚。GPR30在许多细胞和组织中被认为是一种膜雌激素受体。我们发现GPR30在仓鼠卵巢中表达，并作为膜雌激素受体（mER）调节卵巢卵泡的形成和发育。然而，gpr30介导的雌激素调节卵泡发育的机制尚不清楚。同样，GPR30是否在卵巢癌发生中起作用也同样不清楚。我假设雌激素通过GPR30起作用，在生理（卵泡形成和发育的调节）和病理（卵巢癌发生）条件下调节卵巢细胞的增殖、分化和存活。本课题将重点研究GPR30介导的雌激素对原始卵泡形成（K99期）的调控机制，以及GPR30在卵巢癌进展（R00期）中的作用。具体目的为：1)研究GPR30介导的E2在卵巢原始卵泡形成过程中对卵巢细胞增殖、分化、通讯和存活的影响；2)研究GPR30介导E2在卵巢体细胞中的信号传导机制；3)确定GPR30在卵巢癌组织中的表达及其在卵巢癌细胞增殖、侵袭和转移中的作用。K99/R00项目的成功将揭示GPR30对卵巢细胞功能的生理和病理调节机制，为卵巢早衰、卵巢癌等雌激素相关生殖疾病的药物发现和改进治疗提供有价值的信息，并促进我从博士后实习生到独立研究者的职业转变。

DESCRIPTION (provided by applicant): 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 regulate ovarian follicle formation and development. However, the mechanism underlying GPR30-mediated estrogen regulation of follicle development is still unknown. Similarly, whether GPR30 plays a role in ovarian carcinogenesis is equally unclear. I hypothesize that estrogen, acting via GPR30, regulates ovarian cell proliferation, differentiation and survival under both physiological (regulation 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 regulation 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 failure (POF) and ovarian cancer, and facilitate transition of my career from a postdoctoral trainee to independent investigator. PUBLIC HEALTH RELEVANCE: Accomplishment of this project will uncover the mechanisms of GPR30-mediated estrogen action on the regulation of ovarian cell activities under both the physiological and pathological conditions, enrich our knowledge on the membrane estrogen receptor biology and provide new targets for drug discovery, development of new diagnostic tools and advanced management of ovarian cancer.