Potassium channel dysfunction in cerebral arteries

描述（由申请人提供）：我们新颖的、初步的数据导致了这样的假设：“胰岛素是脑循环的重要调节剂，这种作用的强度随着年龄和代谢综合征而受损。”这个重要的研究领域完全没有被探索过。我们的数据首次表明，胰岛素的水平相当于每天进餐时血液中几次达到的水平，能够对脑血管张力和脑血流量（CBF）产生巨大影响。此外，高水平胰岛素对糖尿病患者替代疗法的影响从未被研究过。此外，脑动脉中胰岛素信号级联的许多初始元素与我们发现的促进神经元预处理的元素相似；这导致人们猜测胰岛素对脑血管系统的压力相关损伤具有正常的保护作用。我们的初步数据还表明，胰岛素依赖性对脑血管系统的影响被胰岛素抵抗（IR）（代谢综合征的主要组成部分）或衰老大大降低。然而，恢复正常的脑血管对胰岛素反应的机制和可能的治疗方法尚不清楚。我们将讨论两个具体目标。具体目标胰岛素对脑动脉影响的测定。首先，我们将描述生理和治疗剂量胰岛素对正常SD大鼠脑动脉的影响。其次，我们将研究内皮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，我们将检查胰岛素是否保护脑血管细胞免受致死压力。具体目标2。测定衰老过程中胰岛素对脑动脉的影响及胰岛素抵抗。首先，我们将描述老龄（12-24个月）SD大鼠脑动脉的反应。其次，我们将描述由于摄入高果糖饮食而导致胰岛素抵抗的SD大鼠脑动脉的反应。第三，我们将阐明老龄动物和胰岛素抵抗动物反应改变的机制。第四，我们将研究在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. PUBLIC HEALTH RELEVANCE: Chronic cerebral vascular insufficiency as occurs in IR and in aging and leads to neurological diseases such as non-specific cognitive deficiency, Alzheimer's Disease and strokes but the potential role of insulin has not been studied. Current treatment regimens are not optimal and we expect that the results of our studies will lead to new and improved therapies to prevent or slow the onset of neurological diseases in an obese and aging population.