Pituitary PACAP gene regulation by hypothalamic, pituitary and gonadal factors

下丘脑、垂体和性腺因素对垂体 PACAP 基因的调节

• 批准号: 7179036
• 负责人: LISA M HALVORSON
• 金额: $ 26.06万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7179036
• 关键词: Activins; Adrenal Glands; Anabolism; Animals; Anterior Pituitary Gland; Binding; Biological Models; Cell membrane; Cells; Complex; Cyclic AMP; Cyclic AMP Response Element; Cyclic AMP-Dependent Protein Kinases; DNA; Data; Disease; Elements; Female; G-Protein-Coupled Receptors; Gene Expression; Gene Expression Regulation; Genes; Goals; Gonadal structure; Gonadotrope Cell; Gonadotropin Hormone Releasing Hormone; Gonadotropin-Releasing Hormone Receptor; Gonadotropins; Hormonal; Hormone Responsive; Hormones; Hypothalamic Releasing Factor; Hypothalamic structure; In Vitro; Intestines; Investigation; Islets of Langerhans; Klinefelter' s Syndrome; Lung; Mediating; Messenger RNA; Mitogen-Activated Protein Kinases; Molecular; Neurons; Neuropeptides; Nucleic Acid Regulatory Sequences; Ovarian; Pancreas; Parathyroid gland; Pattern; Peptide Biosynthesis; Peptides; Peripheral Nervous System; Physiological; Physiology; Pituitary Gland; Pituitary Gonadotropins; Placenta; Precocious Puberty; Proestrus; Protein Kinase C; Proteins; Rattus; Regulation; Research Personnel; Role; Signal Pathway; Signal Transduction; Site; Steroids; Syndrome; System; Tissues; Work; autocrine; cell growth regulation; citrate carrier; improved; in vivo; in vivo Model; insight; paracrine; pituitary adenylate cyclase activating polypeptide; polypeptide; promoter; reproductive function; research study; transcription factor

DESCRIPTION (provided by applicant): Recent studies have demonstrated a clear role for pituitary adenylate cyclase-activating peptide (PACAP) in the regulation of gonadotropin biosynthesis and secretion. First defined as a hypothalamic-releasing factor, PACAP subsequently has been determined to have widespread distribution and function, including expression in the gonads, placenta, central and peripheral nervous systems, endocrine pancreas, and adrenal gland. Of particular relevance to this proposal, PACAP expression has been identified in pituitary gonadotrope cells, suggesting that PACAP may act as an autocrine-paracrine factor in this tissue. In view of its critical role in multiple physiologic systems, remarkably little is known regarding the regulation of PACAP gene expression. The primary objective of this proposal is to elucidate the hormonal factors, intracellular signaling systems, transcription factors, and cis-elements which regulate PACAP expression in the pituitary gonadotrope. In preliminary studies, we have observed the ability of gonadotropin-releasing hormone (GnRH) to stimulate PACAP gene expression and have initiated studies to identify GnRH-responsive DNA- regulatory regions in the PACAP gene promoter. The Specific Aims are: 1) To characterize the intracellular signaling pathways which mediate GnRH-activated PACAP gene expression, with a focus on putative AP-1 and CRE-like cis-elements, 2) To identify the transcription factor(s) which mediate GnRH-induced stimulation of PACAP gene promoter activity, 3) To define pituitary PACAP gene expression in primary rat pituitary cells under various physiologic states in vivo, and 4) To characterize the role of pulsatile GnRH, gonadal steroids and gonadal peptides as regulators of PACAP gene expression in vitro. Information obtained regarding the molecular and cellular regulation of PACAP expression is predicted to have broad relevance for the array of physiologic systems in which PACAP functions. More immediately, these studies will provide important insight into the fine-tuning of gonadotrope physiology, a requirement for normal reproductive function. In the longer term, it is predicted that these investigations will broaden our understanding, and ultimately improve treatment options, for the multiple disorders associated with abnormal gonadotropin expression, including delayed and precocious puberty, polycystic ovarian syndrome, and hypogonadotropic hypogonadism.

描述（由申请人提供）：最近的研究表明，垂体腺苷酸环化酶激活肽（PACAP）在促性腺激素生物合成和分泌的调节中起了明显的作用。 PACAP首先被定义为下丘脑释放因子，随后已确定具有广泛的分布和功能，包括在性腺，胎盘，中心和周围神经系统，内分泌胰腺和肾上腺中的表达。与该提案特别相关，PACAP表达已在垂体性促性腺纤维细胞中鉴定出来，这表明PACAP可以在该组织中充当自分泌 - 偏二核因子。鉴于其在多种生理系统中的关键作用，关于PACAP基因表达的调节知之甚少。该提案的主要目的是阐明调节垂体性促性腺瘤中PACAP表达的激素因子，细胞内信号系统，转录因子和顺式元素。在初步研究中，我们观察到促性腺激素释放激素（GNRH）刺激PACAP基因表达的能力，并启动了研究以鉴定PACAP基因启动子中鉴定GNRH反应性DNA-调控区域。具体目的是：1）表征介导GnRH激活的PACAP基因表达的细胞内信号传导途径，重点关注假定的AP-1和类似CRE样的顺式元素，2）识别GNRH介导GnRH介导的PACAP基因启动子启动子的刺激性PACI pacol pacol pacop gene in newarmopic indecial interap pacop gene cenep pacop gene in newarep pacop gene in newarep pacop gene的转录因子，3）体内和4）为表征脉冲GnRH，性腺类固醇和性腺肽的作用，作为PACAP基因表达在体外的调节剂。预计PACAP表达的分子和细胞调节获得的信息被预测与PACAP功能的一系列生理系统具有广泛的相关性。这些研究立即将提供有关促性腺瘤生理学微调的重要见解，这是对正常生殖功能的要求。从长远来看，可以预测，这些研究将扩大我们的理解，并最终改善治疗选择，以促进与促性腺激素异常相关的多种疾病，包括延迟和早熟的青春期，多囊卵巢综合征，以及低胶质性低核对性低核化性。