Cerebrovascular Disease in Type 1 Diabetes

1 型糖尿病引起的脑血管疾病

• 批准号: 6877470
• 负责人: WILLIAM G MAYHAN
• 金额: $ 36.75万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6877470
• 关键词: NAD(P)H oxidoreductase; angiotensin II; carbamates; cardiovascular disorder chemotherapy; cardiovascular disorder prevention; cardiovascular disorder risk; cerebrovascular disorders; chemical structure function; enzyme inhibitors; genetically modified animals; insulin dependent diabetes mellitus; intermolecular interaction; laboratory mouse; laboratory rat; molecular pathology; nitric oxide; nitric oxide synthase; nonhuman therapy evaluation; oxidative stress; phosphorylation; posttranslational modifications; protein kinase C; superoxide dismutase; superoxides; vascular endothelium

DESCRIPTION (provided by applicant): Cerebrovascular dysfunction in diabetes mellitus may be related to alterations in cellular pathways to increase oxidative stress and thus impair nitric oxide synthase (NOS)-dependent reactivity of cerebral vessels. However, cellular/molecular mechanisms by which oxidative stress contributes to cerebrovascular dysfunction remain unknown. We suggest that diabetes impairs reactivity of cerebral vessels by mechanisms that alter several key cellular systems (renin-angiotensin system, protein kinase C, NAD(P)H oxidase, superoxide dismutases and/or endothelial nitric oxide synthase). Alterations in these important enzyme pathways ultimately lead to an increased formation of superoxide anion that can inactivate nitric oxide. Thus, the central hypothesis of this application is that mechanisms contributing to cerebral oxidative stress in diabetes, with consequent effects on nitric oxide bioavailability, lead to impaired reactivity of cerebral vessels. We propose the following specific aims. In specific aim #1, we will test the hypothesis that angiotensin II- dependent activation of NAD(P(H oxidase increases superoxide anion production by cerebral vessels and contributes to cerebrovascular dysfunction in diabetes. In specific aim #2, we will test the hypothesis that diabetes may produce cerebrovascular dysfunction by stimulating superoxide anion production via a protein kinase C-dependent activation of NAD(P)H oxidase. In specific aim #3 we will test the hypothesis that impaired NOS-dependent dilatation of cerebral vessels in diabetic animals may be explained by an uncoupling of eNOS via a reduced availability/utilization of tetrahydrobiopterin (BH4). Finally, in specific aim #-4, we will test the hypothesis that alterations/manipulationns in superoxide dismutases can account for and prevent impaired responses of cerebral vessels in diabetes. We will use state-of-the-art in vivo methodologies coupled with innovative biochemical/molecular/genetic approaches to investigate mechanisms that underlie endothelial dysfunction of cerebral vessels in diabetes. We suggest that our results will provide novel insights regarding therapeutic approaches for the treatment/prevention of cerebrovascular dysfunction in diabetes.

描述（由申请方提供）：糖尿病脑血管功能障碍可能与细胞通路改变有关，从而增加氧化应激，从而损害脑血管的一氧化氮合酶（NOS）依赖性反应性。然而，氧化应激导致脑血管功能障碍的细胞/分子机制仍不清楚。我们认为糖尿病通过改变几个关键细胞系统（肾素-血管紧张素系统、蛋白激酶C、NAD（P）H氧化酶、超氧化物歧化酶和/或内皮型一氧化氮合酶）的机制损害脑血管的反应性。这些重要的酶途径的改变最终导致超氧阴离子的形成增加，超氧阴离子可以抑制一氧化氮。因此，本申请的中心假设是，糖尿病中导致脑氧化应激的机制导致脑血管的反应性受损，从而影响一氧化氮的生物利用度。我们提出以下具体目标。在具体目标#1中，我们将检验血管紧张素II依赖性激活NAD（P（OH）氧化酶增加脑血管产生超氧阴离子并导致糖尿病脑血管功能障碍的假设。在具体目标#2中，我们将检验以下假设：糖尿病可能通过NAD（P）H氧化酶的蛋白激酶C依赖性激活刺激超氧阴离子产生而产生脑血管功能障碍。在具体目标#3中，我们将检验以下假设：糖尿病动物中受损的NOS依赖性脑血管扩张可以通过四氢生物蝶呤（BH 4）的可用性/利用率降低导致eNOS解偶联来解释。最后，在具体目标#-4中，我们将检验超氧化物歧化酶的改变/操纵可以解释和预防糖尿病脑血管反应受损的假设。我们将使用最先进的体内方法，结合创新的生物化学/分子/遗传学方法来研究糖尿病脑血管内皮功能障碍的机制。 我们认为，我们的研究结果将提供新的见解，治疗/预防糖尿病脑血管功能障碍的治疗方法。