GENOMIC & NONGENOMIC EFFECTS OF STEROIDS ON SALT INTAKE

基因组学

• 批准号: 2734152
• 负责人: Randall R. Sakai
• 金额: $ 11.57万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2734152
• 关键词: GABA receptor; aldosterone; amygdala; angiotensin II; antisense nucleic acid; appetite; appetite regulatory center; behavioral genetics; brain metabolism; corticosteroid receptors; genetic regulation; hormone regulation /control mechanism; laboratory rat; salt intake; steroid hormone metabolism

DESCRIPTION: The PI was among the first to demonstrate that sodium appetite is normally caused by a synergistic action of the peptide, angiotensin-II (A-II) and the steroid, aldosterone (ALDO), and he has also been instrumental in beginning to elucidate the receptor mechanisms involved. Because of the rapid elicitation of sodium appetite that can be observed by ALDO in some situations, the PI now proposes several experiments to examine both the genomic and the non-genomic effects of ALDO, to determine specific brain sites where adrenal steroids work to cause sodium appetite, and to interfere with the expression of endogenous steroid receptors in the brain by use of molecular biological techniques and determine the effect upon sodium appetite. In addition to a large behavioral and physiological base, the present research is based on the observation that many brain regions which contain corticosteroid receptors also contain enzymes that reduce the A- ring of steroids, thereby creating molecules which are thought to interact with membrane-bound receptors (possibly the GABAa- benzodiazepine receptor) and hence elicit rapid responses. These are called the non-genomic effects because they do not require the formation of new gene products in order to work. In pilot work, the PI has found that A-ring-reduced metabolites of both ALDO and deoxycorticosterone (DOC, another mineralocorticoid) both elicit rapid sodium appetite in rats. In proposed work, the PI will identify specific brain areas where these metabolites are active, compare their activity to that caused by the parent hormone, and correlate the findings with measurements of activity of the enzymes in the same areas. Although several areas will be investigated, the amygdala is hypothesized to be particularly important since ablation there decreases mineralocorticoid-elicited sodium appetite. Other areas include the medial preoptic area and the paraventricular nuclei. The other series of proposed experiments will investigate genomic control over salt appetite by corticosteroids by using intracranially applied antisense oligomers to the mineralocorticoid (Type I) and glucocorticoid (Type II) receptors. An additional series of experiments will relate the genomic and the non-genomic effects of ALDO. Several models of eliciting sodium appetite will be used in these experiments, and extensive controls are proposed.

描述：PI是最早证明钠的人之一 食欲通常是由肽的协同作用引起的 血管紧张素II（A-II）和类固醇，醛固酮（Aldo），他有 也有助于阐明受体机制 涉及。由于钠的食欲很快 在某些情况下，Aldo可以观察到，PI现在提出了几个 实验以检查基因组和非基因组效应 Aldo，确定肾上腺类固醇工作的特定大脑部位 引起钠的食欲，并干扰 通过使用分子生物学的内源性类固醇受体 技术并确定对钠食欲的影响。 除了庞大的行为和生理基础之外 研究基于以下观察到的许多大脑区域 含有皮质类固醇受体还含有降低A-的酶 类固醇环，从而产生被认为是的分子 与膜结合的受体相互作用（可能是GABAA- 苯二氮卓类受体），因此引起快速反应。这些都是 称为非基因组效应，因为它们不需要形成 新基因产品的工作。在飞行员工作中，PI发现 Aldo和脱氧核心酮的A形降低的代谢产物 （DOC，另一种矿物皮质激素）都在 老鼠。在拟议的工作中，PI将确定特定的大脑区域 这些代谢产物是活跃的，将其活性与 母体激素，并将发现与测量结果相关联 酶在同一地区的活性。虽然有几个领域 被调查，假设杏仁核特别是 重要的是自消融降低矿物皮质激素的降低 钠食欲。其他区域包括内侧前区域和 副核核。 其他一系列提出的实验将研究基因组对照 通过颅内施用皮质类固醇的盐食欲 矿物皮质激素（I型）和糖皮质激素的反义寡聚体 （II型）受体。另一系列实验将相关 Aldo的基因组和非基因组作用。几种模型 这些实验将使用引起钠的食欲，并且 提出了广泛的控制。