Cyclic AMP Signaling in Granulosa Cells

颗粒细胞中的环 AMP 信号转导

• 批准号: 8298917
• 负责人: Anthony J Zeleznik
• 金额: $ 27.16万
• 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/8298917
• 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; Fluorescence Resonance Energy Transfer; Follicle Stimulating Hormone; Forskolin; Gene Expression; Gene Expression Profile; Genes; Goals; Immunoblot Analysis; LH Receptors; Lentivirus Vector; Luteinization; Monitor; Ovarian; Ovarian Follicle; Ovulation; Pathway interactions; 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; mRNA Expression; 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（由申请人提供）：尽管在了解促卵泡激素（FSH）在控制排卵前卵泡发生过程中的作用方面取得了进展，但仍有一个未回答的主要问题是阐明FSH在调节卵泡发育过程中发生的复杂基因表达模式中所利用的细胞内信号传导途径。我们的初步结果指出，通过两个位点FSH可能最佳地诱导颗粒细胞分化。首先，除了PKA之外的一种或多种途径的活化与PKA途径协同作用，以最佳地诱导包括芳香酶和LH受体（与颗粒细胞分化相关的两个标志性基因）在内的基因子集的表达。其次，FSH/cAMP信号通路的区室化可能会导致细胞内cAMP产生与雌激素和孕激素生物合成通路的诱导更有效地偶联。在目前的提案中，我们提出了四个具体目标来解决这些问题。目的1将比较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通过破坏PKA/AKAP与HT 31肽在颗粒细胞分化中的相互作用，并使用基于FRET的新型PKA传感器来直接评估颗粒细胞中cAMP/PKA信号传导系统的区室化，探索颗粒细胞中cAMP/PKA信号传导系统的可能细胞内区室化。了解参与颗粒细胞分化的信号通路可能有助于开发新的避孕药和“生育药物”，以及提供有关可能影响无排卵疾病（如卵巢衰竭和多囊卵巢综合征）的信号通路的新信息。 公共卫生相关性：该项目旨在确定控制卵泡成熟的细胞机制。