Cyclic AMP Signaling in Granulosa Cells

颗粒细胞中的环 AMP 信号转导

• 批准号: 8129801
• 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/8129801
• 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; 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; 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.

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.我们的初步结果指出了两个基因座，FSH可以最佳地诱导颗粒细胞分化。首先，除了PKA与PKA途径协同作用外，激活途径或途径，以最佳诱导基因子集的表达，包括芳香酶和LH受体，这是与颗粒细胞分化相关的两个标志性基因。其次，FSH/CAMP信号通路的分区化可能会导致细胞内cAMP产生的效率更有效，并诱导雌激素和孕酮生物合成途径。在当前的建议中，我们提出了四个特定的目的，以解决这些发现。 AIM 1将比较未分化的颗粒细胞中FSH和PKA-CQR激活的信号通路。 AIM 2将确定哪些信号通路和/或转录因子与PKA相互作用，以最佳诱导颗粒细胞分化。 AIM 3将探索颗粒细胞中营地/PKA信号系统的细胞内隔室化，通过在颗粒细胞分化上与HT31肽的PKA/AKAP相互作用破坏PKA/AKAP相互作用，并使用基于新颖的PKA PKA传感器直接评估Granulululululululululululululululululululosa细胞的CAMP/PKA信号的分裂。了解颗粒细胞分化所涉及的信号传导途径可能对新型避孕药和“生育药物”的发展可能具有重要作用，并提供有关信号通路的新信息，这些信息可能会在卵巢衰竭和多囊性卵巢综合征等发型疾病中受到影响。 公共卫生相关性：该项目旨在确定控制卵巢卵泡成熟的细胞机制。