GPR30 Mediated-Estrogen Action on Ovarian Physiology and Ovarian Cancer

性状（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，卵巢中的许多病理状况导致女性不孕症和诸如卵巢癌的疾病。我的长期目标是确定有助于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（E2）在卵巢的生理和病理中起着重要作用，但其作用机制尚不清楚。GPR 30在许多细胞和组织中被认为是膜雌激素受体（mER）。我们已经证明GPR 30在仓鼠卵巢中表达，并作为膜雌激素受体（mER）调节卵泡的形成和发育。然而，GPR 30介导的雌激素调节卵泡发育的机制仍不清楚。同样，GPR 30是否在卵巢癌发生中起作用也同样不清楚。我推测，雌激素，通过GPR 30，调节卵巢细胞增殖，分化和生存的生理（卵泡形成和发育的调节）和病理（卵巢癌）条件下。该提案将集中于GPR 30介导的雌激素作用于原始卵泡形成（K99期）的调节的机制，以及GPR 30在卵巢癌进展（R 00期）中的功能。具体目标是：1）检测GPR 30介导的E2对原始卵泡形成期间卵巢细胞的增殖、分化、通讯和存活的作用，2）检测GPR 30在卵巢体细胞中介导E2作用的信号传导机制，和3）确定GPR 30在卵巢癌组织中的表达和GPR 30在增殖中的功能，卵巢癌细胞的侵袭和转移。该K99/R 00项目的完成将揭示GPR 30对卵巢细胞功能的生理和病理调节机制，为药物发现和改善卵巢早衰（POF）和卵巢癌等雌激素相关生殖疾病的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过渡。 公共卫生相关性：该项目的完成将揭示GPR 30介导的雌激素在生理和病理条件下调节卵巢细胞活性的机制，丰富我们对膜雌激素受体生物学的认识，并为药物发现，开发新的诊断工具和卵巢癌的先进管理提供新的靶点。

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.