Potassium channel dysfunction in cerebral arteries

描述(由申请人提供)：我们的新的初步数据导致了这样的假设：“胰岛素是大脑循环的重要调节器，这种影响的大小随着年龄的增长和代谢综合征的出现而受损。”这一重要的研究领域完全没有被探索过。我们的数据首次表明，胰岛素水平相当于每天用餐期间血液中达到的水平，能够对脑血管张力和脑血流量(CBF)产生显著影响。此外，与糖尿病患者的替代治疗相关的高水平胰岛素的作用从未被研究过。此外，大脑动脉中胰岛素信号级联反应的许多初始元件与我们已发现的促进神经元预适应的元件相似；这导致人们猜测，胰岛素对脑血管系统的应激相关损伤具有正常的保护作用。我们的初步数据还表明，胰岛素对脑血管系统的依赖效应因胰岛素抵抗(IR)或衰老而大大降低，IR是代谢综合征的主要组成部分。然而，恢复正常脑血管对胰岛素的反应性的机制和可能的治疗方法尚不清楚。我们将解决两个具体目标。具体目的1.胰岛素对脑动脉作用的测定。首先，我们将表征生理剂量和治疗剂量的胰岛素对正常SD大鼠脑动脉的影响。其次，我们将研究血管内皮细胞和平滑肌在血管张力综合变化中的作用。第三，我们将研究胰岛素受体激活后的信号级联反应。第四，我们将研究介导胰岛素对脑动脉影响的血管活性物质的性质。第五，我们将研究胰岛素是否能保护脑血管细胞免受致命压力的伤害。具体目的2.测定胰岛素在衰老和胰岛素抵抗期间对脑动脉的影响。首先，我们将描述老年(12-24个月)SD大鼠脑动脉的反应。其次，我们将描述因摄入高果糖饮食而患胰岛素抵抗的SD大鼠的脑动脉反应。第三，我们将阐明老年和胰岛素抵抗动物反应改变的机制。第四，我们将研究在存在IR或衰老的情况下恢复正常脑动脉对胰岛素反应的治疗方法。

DESCRIPTION (provided by applicant): Our novel, preliminary data have lead to the hypothesis that "insulin is an important regulator of the cerebral circulation and that the magnitude of this effect is impaired with aging and the metabolic syndrome." This important research area is totally unexplored. Our data show for the first time that insulin, at levels which are equivalent to those reached in blood several times each day during meals, is able to have dramatic effects on cerebral vascular tone and cerebral blood flow (CBF). In addition, the effect of insulin at very high levels which are associated with replacement therapy in diabetic patients has never been investigated. Furthermore, many of the initial elements of the insulin signaling cascade in cerebral arteries are similar to those that we have found to promote neuronal preconditioning; leading to speculation that insulin has a normal, protective effect against stress-related damage in the cerebral vasculature. Our preliminary data also indicate that insulin-dependent effects on the cerebral vasculature are greatly reduced by insulin resistance (IR), a major component of the metabolic syndrome, or by aging. However, mechanisms and possible therapeutic approaches for the restoration of normal cerebral vascular responsiveness to insulin are unknown. We will address two specific aims. Specific Aim 1. Determination of the effects of insulin on cerebral arteries. First, we will characterize the effects of physiological and therapeutic doses of insulin on cerebral arteries of normal Sprague Dawley (SD) rats. Second, we will examine the roles of endothelium and smooth muscle on the integrative changes in vascular tone. Third, we will examine the signaling cascades following activation of insulin receptors. Fourth, we will examine the nature of vasoactive substances mediating insulin effects on the cerebral arteries. Fifth, we will examine whether insulin protects cerebral vascular cells against lethal stress. Specific Aim 2. Determination of the effects of insulin on cerebral arteries during aging and insulin resistance. First, we will characterize responses in cerebral arteries in aged (12-24 month) SD rats. Second, we will characterize responses in cerebral arteries from SD rats suffering from insulin resistance due to consumption of a diet high in fructose. Third, we will elucidate the mechanisms of altered responses in aged and insulin resistant animals. Fourth, we will examine therapeutic approaches for the restoration of normal cerebral arterial responses to insulin in the presence of IR or aging.