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

基本信息

批准号：
7623206
负责人：
LISA M HALVORSON
金额：
$ 25.54万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/7623206
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&apos 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

项目摘要

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具有明确的作用。 PACAP 首先被定义为下丘脑释放因子，随后被确定具有广泛的分布和功能，包括在性腺、胎盘、中枢和周围神经系统、内分泌胰腺和肾上腺中表达。与该提议特别相关的是，PACAP 在垂体促性腺细胞中表达，表明 PACAP 可能在该组织中充当自分泌-旁分泌因子。鉴于其在多种生理系统中的关键作用，人们对 PACAP 基因表达的调控知之甚少。该提案的主要目的是阐明调节垂体促性腺激素中 PACAP 表达的激素因子、细胞内信号系统、转录因子和顺式元件。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，并已启动研究以确定 PACAP 基因启动子中的 GnRH 响应性 DNA 调控区域。具体目标是：1) 表征介导 GnRH 激活的 PACAP 基因表达的细胞内信号通路，重点关注推定的 AP-1 和 CRE 样顺式元件，2) 鉴定介导 GnRH 激活的 PACAP 基因表达的转录因子GnRH 诱导的 PACAP 基因启动子活性刺激，3) 定义体内各种生理状态下原代大鼠垂体细胞中垂体 PACAP 基因的表达，4) 表征脉动 GnRH、性腺类固醇和性腺肽作为体外 PACAP 基因表达调节剂的作用。预计获得的有关 PACAP 表达的分子和细胞调节的信息与 PACAP 发挥功能的一系列生理系统具有广泛的相关性。更直接的是，这些研究将为促性腺激素生理学的微调提供重要的见解，这是正常生殖功能的要求。从长远来看，预计这些研究将拓宽我们的理解，并最终改善与促性腺激素表达异常相关的多种疾病的治疗选择，包括青春期延迟和早熟、多囊卵巢综合征和促性腺激素低下性性腺功能减退症。