ALPHA-1 ADRENERGIC RESPONSES IN SMOOTH MUSCLE

描述：(改编自调查人员摘要)这项计划的目标 建议侧重于α1肾上腺素能受体的作用 在血管平滑肌中，强调对这些受体的调节 以及它们的信号机制。具体目标1：信号转导 血管平滑肌中α受体的作用机制。在.期间 在过去的资助期内，调查人员开发出的证据表明 血管平滑肌中的α1受体激活了多种 信号通路包括MAP激酶和原癌基因的表达。 这个目标的主要目的是描述α1刺激的特征 这些以及血管平滑肌中的其他信号通路。自.以来 他们发现，一氧化氮可以抑制原核糖核酸的激活。 癌基因在完整的主动脉中的表达，这一目标的第二个方面是 确定一氧化氮修饰的信号机制 对α1受体刺激的反应。这个目标的第三个方面 是为了确定在这些信号通路中的改变 延长后的平滑肌脱敏α-1反应 α1肾上腺素能受体的激活。具体目标2：差异化 α1受体与信号通路的偶联。在预赛中 实验中，研究人员发现，特异的α1受体 亚型有不同的信号机制或诱导能力 培养细胞中的基因表达。这个目标的目的是 进一步描述这些不同效应的机制 α1肾上腺素能受体亚型。他们建议将这一点应用于 研究信号机制的信息涉及 α1B受体的结构性活性突变导致 即使在没有细胞分裂的情况下也能刺激转基因细胞分裂 儿茶酚胺。特定目标3：α1受体的代谢作用 在血管平滑肌和基因调控方面。他们发现， 胰岛素和IGF-1诱导特定α1受体亚型的表达 在血管平滑肌细胞中。另外，他们的初步结果 提示α1受体的激活诱导低密度脂蛋白的表达 平滑肌细胞中的受体和脂质摄取。这些结果可能 对高架飞机的不利影响有机械上的影响 高血压病患者的胰岛素水平及其对血压的影响 阿尔法肾上腺素能拮抗剂对心血管风险的影响。这样做的目的是 具体目的是扩大和深化对这些影响的观察 胰岛素和α1激动剂对血管细胞生物学的影响。 拟议的实验对以下方面具有特别的相关性 α1受体在血管中的药理作用 潜在机制在以下方面应具有更广泛的重要性 了解这些受体的生物学特性，这些受体转导许多 交感神经系统在健康和疾病中的作用。

DESCRIPTION: (Adapted from investigator's abstract) The goals of this proposal focus on the action of alpha1 adrenergic receptors particularly in vascular smooth muscle with emphasis on regulation of these receptors and their signaling mechanisms. Specific Aim 1: Signal transduction mechanisms of alpha receptors in vascular smooth muscle. During the past funding period the investigators have developed evidence indicating that alpha1 receptors in vascular smooth muscle activate a variety of signaling pathways including MAP kinases and proto-oncogene expression. The primary purpose of this aim is to characterize alpha1 stimulation of these and other signaling pathways in vascular smooth muscle. Since they have found that nitric oxide inhibits the activation of proto- oncogene expression in intact aortas, the second aspect of this aim is to identify signaling mechanisms by which nitric oxide modifies responses to alpha1 receptor stimulation. The third aspect of this aim is to determine alterations in these signaling pathways induced by desensitizing alpha1 responses in smooth muscle after prolonged activation of alpha1 adrenergic receptors. Specific Aim 2: Differential coupling of alpha1 receptors to signaling pathways. In preliminary experiments, the investigators have found that specific alpha1 receptor subtypes have different signaling mechanisms or capacities to induce gene expression in cultured cells. The purpose of this aim is to characterize further the mechanisms for these differential effects of alpha1 adrenergic receptor subtypes. They propose to apply this information to investigate the signaling mechanisms involving a constitutively active mutation of the alpha1B receptor which leads to stimulation of cell division in transfected cells even in the absence of catecholamines. Specific Aim 3: Metabolic effects of alpha1 receptors in vascular smooth muscle and gene regulation. They have found that insulin and IGF-1 induce expression of specific alpha1 receptor subtypes in vascular smooth muscle cells. Also, their preliminary results indicate that activation of alpha1 receptors induces expression of LDL receptors and lipid uptake in smooth muscle cells. These results may have mechanistic implications for the adverse effects of elevated insulin concentrations in hypertension and the beneficial effects of alpha adrenergic antagonists on cardiovascular risk. The purpose of this specific aim is to extend and deepen these observations of the effects of insulin and alpha1 agonists on vascular cell biology. The proposed experiments have particular relevance for the pharmacological role of alpha1 receptors in blood vessels; as well, the underlying mechanisms should have more general importance in understanding the biology of these receptors which transduce many of the actions of the sympathetic nervous system in health and disease.