GPR30 Mediated-Estrogen Action on Ovarian Physiology and Ovarian Cancer

描述(申请人提供)：哺乳动物卵巢不仅为生殖提供卵子，还提供维持正常生理的雌性激素。然而，卵巢中的许多病理情况会导致女性不孕和卵巢癌等疾病。我的长期目标是确定导致卵巢生理和病理变化的分子，以便开发新的诊断或治疗方法来改善妇女的健康。雌激素在卵巢的生理和病理中起着重要的作用，但其作用机制尚不清楚。GPR30在许多细胞和组织中被认为是一种膜雌激素受体(Mer)。我们已经证明GPR30在仓鼠卵巢中表达，并作为膜雌激素受体(Mer)来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仍不清楚。同样，GPR30是否在卵巢癌的发生中起作用也同样不清楚。我假设，雌激素通过GPR30作用，在生理(调节卵泡形成和发育)和病理(卵巢癌变)条件下调节卵巢细胞的增殖、分化和存活。本研究将侧重于GPR30介导的雌激素调节原始卵泡形成(K99期)的机制，以及GPR30在卵巢癌进展(R00期)中的作用。其具体目的是：1)研究GPR30介导的E2在原始卵泡形成过程中对卵巢细胞增殖、分化、通讯和存活的作用；2)研究GPR30在卵巢体细胞中介导E2作用的信号机制；3)检测GPR30在卵巢癌组织中的表达以及GPR30在卵巢癌细胞增殖、侵袭和转移中的作用。这项K99/R00计划的完成将有助于阐明GPR30对卵巢细胞功能的生理和病理调节机制，为药物开发和卵巢早衰(POF)和卵巢癌等雌激素相关生殖疾病的改进治疗提供有价值的信息，并促进我的职业生涯从博士后实习生过渡到独立研究人员。 公共卫生意义：该项目的完成将揭示GPR30介导的雌激素在生理和病理条件下调节卵巢细胞活动的机制，丰富我们对细胞膜雌激素受体生物学的认识，并为卵巢癌的药物发现、新诊断工具的开发和先进的治疗提供新的靶点。

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.