Cyclic AMP Signaling in Granulosa Cells

颗粒细胞中的环 AMP 信号转导

• 批准号: 7983717
• 负责人: Anthony J Zeleznik
• 金额: $ 28.29万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7983717
• 关键词: A kinase anchoring protein; AKAP13 gene; Accounting; Address; Adenoviruses; Affect; Aromatase; Biosensor; Cell Differentiation process; Cell Extracts; Cell Nucleus; Complex; Contraceptive Agents; Coupling; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cytoplasm; Development; Disease; Dose; Estradiol; Estrogens; Failure; Fertility Agents; Follicle Stimulating Hormone; Forskolin; Gene Expression; Genes; Goals; Immunoblot Analysis; LH Receptors; Lentivirus Vector; Luteinization; Monitor; Ovarian; Ovarian Follicle; Ovulation; Pathway interactions; Pattern; Peptides; Process; Production; Progesterone; Regulation; Reporter; Reporting; Research; Role; Signal Pathway; Signal Transduction; Study Section; Syndrome; System; Testing; Time; Undifferentiated; Viral Vector; Western Blotting; base; folliculogenesis; granulosa cell; novel; public health relevance; reproductive success; response; sensor; transcription factor

DESCRIPTION (provided by applicant): Although progress has been made in understanding the role of follicle stimulating hormone (FSH) in governing the process of preovulatory folliculogenesis, a major question that remains unanswered is the elucidation of the intracellular signaling pathways utilized by FSH in the regulation of the complex pattern of gene expression that occurs during follicular development. Our preliminary results point to two loci through which FSH may optimally induce granulosa cell differentiation. First, activation of a pathway or pathways in addition to PKA synergizes with the PKA pathway to optimally induce the expression of a subset of genes including aromatase and the LH receptor, the two hallmark genes associated with granulosa cell differentiation. Second, compartmentalization of the FSH/cAMP signaling pathway may result in more efficient coupling of intracellular cAMP production with the induction of the estrogen and progesterone biosynthetic pathways. In this current proposal we present four Specific Aims to address these findings. Aim 1 will compare the signaling pathways activated by FSH and by PKA-CQR in undifferentiated granulosa cells. Aim 2 will determine which signaling pathways and/or transcription factors interact with PKA to optimally induce granulosa cell differentiation. Aim 3 will explore the possible intracellular compartmentalization of the cAMP/PKA signaling system in granulosa cells by disrupting PKA/AKAP interactions with HT31 peptides on granulosa cell differentiation and using novel FRET-based PKA sensors to directly evaluate compartmentalization of cAMP/PKA signaling in granulosa cells. Understanding the signaling pathways involved in granulosa cell differentiation may be instrumental for the development of novel contraceptives and "fertility drugs" as well as providing new information regarding signaling pathways that may be affected in anovulatory disorders such as ovarian failure and polycystic ovarian syndrome. PUBLIC HEALTH RELEVANCE: This project seeks to identify the cellular mechanisms that control the maturation of the ovarian follicle.

描述(申请人提供)：尽管卵泡刺激素(FSH)在控制排卵前卵泡发生过程中的作用已经取得了进展，但一个尚未回答的主要问题是FSH在调控卵泡发育过程中复杂的基因表达模式中所使用的细胞内信号通路的阐明。我们的初步结果指出，FSH可以通过两个基因位点最佳地诱导颗粒细胞分化。首先，除了PKA外，一个或多个途径的激活与PKA途径协同作用，以最佳地诱导包括芳香化酶和促黄体生成素受体在内的一组基因的表达，这两个标记基因与颗粒细胞分化有关。其次，FSH/cAMP信号通路的区段化可能导致细胞内cAMP产生与雌激素和孕激素生物合成通路的诱导更有效地耦合。在目前的提案中，我们提出了四个具体目标来处理这些调查结果。目的1比较FSH和PKA-CQR在未分化颗粒细胞中激活的信号通路。目的2将确定哪些信号通路和/或转录因子与PKA相互作用，以最佳地诱导颗粒细胞分化。目的3通过阻断颗粒细胞分化过程中PKA/AKAP与HT31多肽的相互作用，并使用基于FRET的新型PKA传感器直接评价颗粒细胞内cAMP/PKA信号的区划，探讨cAMP/PKA信号系统在颗粒细胞内的区划。了解颗粒细胞分化所涉及的信号通路可能有助于开发新的避孕药和生育药物，并为卵巢衰竭和多囊卵巢综合征等无排卵性疾病可能影响的信号通路提供新的信息。 公共卫生相关性：该项目寻求确定控制卵巢卵泡成熟的细胞机制。