GENOMIC & NONGENOMIC EFFECTS OF STEROIDS ON SALT INTAKE

描述：PI是最早证明钠 食欲通常是由多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 也在开始阐明受体机制方面发挥了重要作用 牵涉其中。因为钠的食欲迅速激发，可以 在某些情况下被Aldo观察，PI现在提出了几个 同时检测基因组和非基因组效应的实验 Aldo，以确定肾上腺类固醇作用于 引起钠的食欲，并干扰其表达 脑内内源性类固醇受体的分子生物学研究 技术，并确定对钠食欲的影响。 除了巨大的行为和生理基础外，目前 这项研究的基础是观察到许多大脑区域 含有皮质类固醇受体也含有酶，可以减少A- 类固醇的环，从而产生被认为是 与膜结合受体相互作用(可能是GABAA- 苯二氮卓类受体)，从而引起快速反应。这些是 被称为非基因组效应，因为它们不需要形成 新的基因产品才能发挥作用。在试点工作中，公安局发现 Aldo和脱氧皮质酮的A环还原代谢物 (DOC，另一种矿物皮质激素)两者都能引起大鼠快速的钠摄取 老鼠。在拟议的工作中，PI将识别特定的大脑区域， 这些代谢物是活性的，将它们的活性与 母体荷尔蒙，并将这些发现与测量 这些酶在相同区域的活性。尽管有几个领域将 被调查，杏仁核被认为是特别的 重要的是，自消融以来，减少了由矿物皮质激素引起的 钠的食欲。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。 脑内应用糖皮质激素引起的食盐量增加 针对盐皮质激素(I型)和糖皮质激素的反义寡聚体 (II)受体。另外一系列实验将与 Aldo的基因组和非基因组效应。几种型号的 在这些实验中，将使用激发钠的食欲，以及 提出了广泛的控制措施。

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.