NUCLEAR EFFECTS OF ANGIOTENSIN ON VASCULAR SMOOTH MUSCLE

血管紧张素II(Ang II)是一种生理活性八肽， 在心血管动态平衡中发挥重要作用 肾脏和电解质调节。这种多肽能诱导出不同的 一些回应是立即发生的，但另一些回应，如法规 基因表达和生长调控被推迟 相当可观。Ang II带来的许多短期影响是 与跨膜信号转导机制有关。 越来越多的证据表明，Ang II可能也有 直接的核效应。这一核行动至少可以解释 在一定程度上，这是由于Ang II的一些延迟的长期影响。 这项建议的总体目标是研究 分子水平上的核效应。 我们已经证明了特定的、可饱和的血管紧张素Ⅱ受体的存在。 在肝细胞的细胞核中。这些受体将是 具有更详细的特征，通过确定 结合各种血管紧张素片段和类似物。这些 特性将与质膜的特性进行比较。 Ang 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--核受体调控的研究 然后就会被启动。已知可调节的扰动 血浆Ang II受体将被用来确定是否 血浆和核受体是平行调节的。我们会 然后用标准层析法纯化该受体 技巧。 为了确定这种受体的作用机制， 血管紧张素受体复合体与基因组DNA的相互作用 使用肾素基因的调节区作为研究对象 一个模范系统。产生血管紧张素所必需的序列 对基因的反应性将通过分子水平来确定 生物技术。这些研究的结果应该大大 增加我们对这一重要因素作用机制的认识 应进一步提高对多肽的认识 一般都是荷尔蒙。

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.