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是第一个证明钠 食欲通常由肽的协同作用引起， 血管紧张素-II（A-II）和类固醇，醛固酮（ALDO），他有 也有助于开始阐明受体机制 涉案由于快速激发钠的食欲， 在某些情况下，ALDO观察到，PI现在提出了几个 实验，以检查基因组和非基因组的影响， ALDO，以确定肾上腺皮质类固醇发挥作用的特定大脑部位， 引起钠的食欲，并干扰表达 内源性类固醇受体在大脑中的分子生物学应用 技术，并确定对钠食欲的影响。 除了大量的行为和生理基础外， 这项研究是基于对大脑中许多区域的观察， 含有皮质类固醇受体，也含有减少A- 类固醇环，从而产生被认为是 与膜结合受体相互作用（可能是GABA a- 苯二氮卓受体），并因此引起快速反应。这些是 称为非基因组效应，因为它们不需要形成 新的基因产物才能发挥作用。在试点工作中，PI发现 ALDO和脱氧皮质酮的A环还原代谢物 (DOC，另一种盐皮质激素）都能引起快速的钠食欲， 大鼠在拟议的工作中，PI将确定特定的大脑区域， 这些代谢物是活性的，将它们的活性与 母体激素，并将结果与测量结果相关联， 酶在同一区域的活性。虽然有几个领域将 研究，杏仁核被假设为特别是 这很重要，因为消融可以减少盐皮质激素引起的 钠食欲其他区域包括内侧视前区和 室旁核 另一系列拟议的实验将研究基因组控制 通过使用颅内应用的皮质类固醇引起的过度盐食欲 盐皮质激素（I型）和糖皮质激素的反义寡聚体 (Type II）受体。另外一系列的实验将涉及 ALDO的基因组和非基因组效应。几种型号的 在这些实验中将使用引发钠食欲的药物， 提出了广泛的控制措施。