NUCLEAR EFFECTS OF ANGIOTENSIN ON VASCULAR SMOOTH MUSCLE

血管紧张素II（AngII）是一种具有生理活性的八肽， 在心血管稳态中起着重要作用， 肾脏和电解质调节。 这种肽诱导多种 反应，有些立即发生，但其他如监管 基因表达和生长调节， 相当大。 血管紧张素II引起的许多短期效应是 与跨膜信号转导机制有关。 越来越多的证据表明，血管紧张素II也可能具有 直接的核效应。 这次核行动至少可以说明 部分原因是血管紧张素II的一些延迟的长期作用。 的 本提案的总体目标是研究 分子水平上的核效应。 我们已经证明了特异性的、可饱和的血管紧张素II受体的存在， 在肝细胞核中。 这些受体将 其特征在于更详细地通过确定以下物质的特异性来表征： 各种血管紧张素片段和类似物的结合。 这些 特性将与质膜的特性进行比较 血管紧张素II受体，以确定核受体是否相似或 如果它代表一种新的结合蛋白。 一旦我们确定了 核受体，对该受体调节的研究 将被启动。 已知的扰动 血浆血管紧张素II受体将被用来确定是否 血浆和核受体是平行调节的。 我们将 然后使用标准色谱法纯化该受体， 技术. 为了确定该受体的作用机制， Ang-Nuclear受体复合物与基因组DNA相互作用将 使用肾素基因的调节区作为 一个模型系统 赋予血管紧张素 对基因的反应性将使用分子生物学方法来确定。 生物技术 这些研究的结果应该大大 增加我们对这一重要的作用机制的了解， 肽，并应进一步增加我们对肽的理解 荷尔蒙一般。

Angiotensin II (Ang II), a physiologically active octapeptide, plays an important role in cardiovascular homeostasis as well as renal and electrolyte regulation. This peptide induces diverse responses, some occur immediately but others such as the regulation of gene expression and modulation of growth, are delayed considerably. Many short term effects elicited by Ang II are associated with transmembrane signal transduction mechanisms. Evidence is accumulating which suggests that Ang II may also have a direct nuclear effect. This nuclear action may account, at least in part, for some of the delayed, long term effects of Ang II. The overall goal of this proposal is to study the mechanism of the nuclear effect at the molecular levels. We have shown the presence of specific, saturable Ang II receptors in the nuclei of liver cells. These receptors will be characterized in greater detail by determining the specificity of binding of various angiotensin fragments and analogous. These characteristics will be compared to those of the plasma membrane Ang II receptor to determine if the nuclear receptor is similar or if it represents a new binding protein. Once we have characterized the nuclear receptor, a study of the regulation of this receptor will then be initiated. Perturbations which are known to regulate the plasma Ang II receptor will be employed to determine if the plasma and nuclear receptors are regulated in parallel. We will then purify this receptor using standard chromatographic techniques. To determine the mechanism of action of this receptor, the interaction of Ang-nuclear receptor complex with genomic DNA will be investigated using the regulatory regions of the renin gene as a model system. The sequence necessary to confer angiotensin responsiveness to a gene will be determined using molecular biological techniques. The results of these studies should greatly increase our knowledge of the mechanism of action of this important peptide and should further increase our understanding of peptide hormones in general.