Ad-vectors and Granulosa Cell Signaling

Ad 载体和颗粒细胞信号传导

• 批准号: 7271162
• 负责人: Anthony J Zeleznik
• 金额: $ 25.34万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7271162
• 关键词: 1-Phosphatidylinositol 3-Kinase; Activins; Address; Adopted; Affect; Aromatase; Cell Differentiation process; Cell Proliferation; Cell physiology; Complex; Contraceptive Agents; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Development; Differentiation and Growth; Dominant-Negative Mutation; Enzymes; Estradiol; Estrogens; Female; Fertility Agents; Follicle Stimulating Hormone; Follicle Stimulating Hormone Receptor; Funding; Gene Expression; Homologous Gene; Hormone Receptor; Individual; LH Receptors; Liver; Luteinizing Hormone; Mediating; Nuclear Orphan Receptor; Ovarian; Ovarian Follicle; PCNA gene; Pathway interactions; Pattern; Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide; Play; Process; Production; Progesterone; Proteins; Proto-Oncogene Proteins c-akt; Regulation; Reproduction; Research; Role; Signal Pathway; Signal Transduction; Signaling Protein; Specificity; Steroid biosynthesis; System; cell type; cyclin D2; defective adenoviral vector; folliculogenesis; granulosa cell; in vivo; inhibitor/antagonist; next generation; novel; protein expression; receptor; vector

DESCRIPTION (provided by applicant): Although progress has been made in understanding the individual roles of follicle stimulating hormone (FSH) an luteinizing hormone (LH) in governing the process of preovulatory folliculogenesis, a major question which remains unanswered is the elucidation of the intracellular signaling pathways utilized by FSH and LH in their regulation of the complex pattern of gene expression that occurs during follicular development. The research proposed herein will make use of replication-defective adenovirus vectors to explore the signaling pathways involved in granulosa cell proliferation and differentiation. Because these vectors infect granulosa cells and direct the expression of proteins with high efficiency it is possible to express constitutively activated as well as dominant-negative signaling proteins and directly assess their influences on granulosa cell steroidogenesis and cAMP production as well as the expression of mRNAs that encode for differentiation and proliferation-associated proteins. Aim 1will elucidate the mechanism by which FSH activates the PI3- kinase/PKB intracellular signaling pathway in granulosa cells. Aim 2 will identify downstream effectors of PI3-kinase/ PKB signaling system in granulosa cells that govern granulosa cell differentiation. Aim 3 will determine if LRH-1 and/or SF-1 are necessary and sufficient for cAMP-induced expression of mRNAs for enzymes involved in progesterone, but not estrogen, production during granulosa cell differentiation and to determine if SF-1 and LRH-1 are equally effective in this regard and Aim 4 will identify the intracellular signaling pathways responsible for the synergistic role of activin in FSH-stimulated granulosa cell proliferation. Understanding the intracellular signaling pathways utilized by the FSH receptor and the LH receptor will be instrumental for the development of the next generation of contraceptives as well as the next generation of "fertility drugs" in which FSH and LH signaling pathways are targeted directly. In addition, results may provide new information regarding signaling pathways that may be affected in PCOS.

描述（由申请人提供）：尽管在了解促卵泡激素（FSH）和促黄体生成激素（LH）在控制排卵前卵泡发生过程中的个体作用方面取得了进展，但仍有一个尚未回答的主要问题是阐明FSH和LH在调节卵泡发育过程中发生的复杂基因表达模式时所利用的细胞内信号传导途径。本研究将利用复制缺陷型腺病毒载体来探索颗粒细胞增殖和分化的信号通路。由于这些载体感染颗粒细胞并高效地指导蛋白质的表达，因此可以表达组成型激活的以及显性负信号蛋白，并直接评估它们对颗粒细胞类固醇生成和cAMP产生以及编码分化和增殖相关蛋白的mRNA表达的影响。目的1阐明FSH激活颗粒细胞PI 3- kinase/PKB信号通路的机制。目的二是研究颗粒细胞中PI 3-kinase/ PKB信号系统下游调控颗粒细胞分化的分子。目的3将确定LRH-1和/或SF-1是否是cAMP诱导的孕酮相关酶mRNA表达所必需和充分的，但不是雌激素，为了确定SF-1和LRH-1在这方面是否同样有效，Aim 4将确定负责激活素在FSH-1中协同作用的细胞内信号通路。刺激颗粒细胞增殖。了解FSH受体和LH受体所利用的细胞内信号通路将有助于开发下一代避孕药以及下一代直接靶向FSH和LH信号通路的“生育药物”。此外，研究结果可能提供有关PCOS可能受影响的信号通路的新信息。