Influence of ExT on Cerebrovacsular Dysfunction in T1D

ExT 对 1 型糖尿病脑血管功能障碍的影响

• 批准号: 8046387
• 负责人: WILLIAM G MAYHAN
• 金额: $ 36万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8046387
• 关键词: Accounting; Animals; Antioxidants; Biochemical; Biochemical Genetics; Biological Availability; Brain; Brain Diseases; Brain Injuries; Cardiovascular Diseases; Cerebrovascular Disorders; Cerebrum; Coupled; Development; Dilatation - action; Equilibrium; Exercise; Functional disorder; Health; Human; Impaired cognition; Impairment; Infarction; Inflammatory Response; Insulin-Dependent Diabetes Mellitus; Ischemia; Ischemic Brain Injury; Lead; Measures; Microcirculation; Middle Cerebral Artery Occlusion; Molecular; Morbidity - disease rate; Nitric Oxide; Nitric Oxide Synthase; Oxidants; Oxidases; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Physiological; Potassium; Potassium Channel; Proteins; Reactive Oxygen Species; Regulation; Renin-Angiotensin System; Role; Stimulus; Stroke; Superoxides; Techniques; Testing; Therapeutic; Therapeutic Intervention; Training; Very Light Exercise; arteriole; biological adaptation to stress; cerebrovascular; genetic manipulation; in vivo; innovation; mortality; novel therapeutic intervention; prevent; response; type I diabetic

DESCRIPTION (provided by applicant): Cardiovascular disease is a major cause of morbidity and mortality in patients with Type 1 diabetes (T1D). In addition, cerebrovascular dysfunction contributes to the pathogenesis of stroke and cognitive impairment observed in humans with T1D. These consequences of T1D may be related to alterations in cellular networks that increase oxidative stress, and impair nitric oxide synthase (NOS) and potassium (K+) channel- dependent reactivity of cerebral vessels. We suggest that T1D impairs reactivity of cerebral vessels by altering the balance between key cellular networks responsible for governing oxidative stress, and thus reducing nitric oxide (NO) bioavailability and produce K+ channel dysfunction. We also have evidence suggesting that exercise training (ExT) may restore this balance. Our central hypothesis is that T1D alters the contribution of oxidative cellular networks governing cerebrovascular reactivity, and that ExT will alleviate cerebrovascular dysfunction during T1D via effects on these cellular networks. To test this hypothesis, the following aims are proposed. In Specific Aim #1, we will test the hypothesis that the contribution of NOS and K+ channels in the regulation of cerebrovascular function is impaired in T1D and that ExT will alleviate/prevent this impairment. In Specific Aim #2, we will test the hypothesis that T1D impairs NOS- and K+ channel-dependent responses of cerebral vessels via activation of cellular networks that lead to an increase in oxidative stress and that ExT can alleviate cerebrovascular dysfunction by influencing these critical networks. In Specific Aim #3, we will test the hypothesis that alterations/manipulations in antioxidant pathways may contribute to impaired responses of cerebral vessels during T1D and that ExT can alleviate this impairment by influencing these antioxidant pathways. In Specific Aim #4, we will test the hypothesis that ExT can reduce cerebral ischemic brain damage during T1D mainly via its influence on oxidative stress. Our studies will be the first comprehensive and integrative attempt to examine mechanisms that contribute to impaired reactivity of cerebral vessels during T1D and the therapeutic benefits of ExT on cerebral vessels and brain damage during T1D. We will use established techniques to examine in vivo reactivity of cerebral vessels coupled with new innovative molecular and biochemical approaches to determine the effects of T1D and ExT on the brain. PUBLIC HEALTH RELEVANCE: While T1D contributes to many disorders of the brain, including stroke, cellular mechanisms that account for the effects of T1D on the brain remain virtually unknown. ExT may be a valid therapeutic approach for the treatment of brain dysfunction during T1D, however, no studies have examined this approach for the treatment of cerebrovascular dysfunction during T1D. Our studies will be the first to examine the potential therapeutic benefits of ExT on brain function during T1D.

描述（由申请人提供）：心血管疾病是 1 型糖尿病 (T1D) 患者发病和死亡的主要原因。此外，脑血管功能障碍导致中风和认知障碍的发病机制，在 1 型糖尿病患者中观察到。 T1D 的这些后果可能与细胞网络的改变有关，这些改变会增加氧化应激，并损害脑血管的一氧化氮合酶 (NOS) 和钾 (K+) 通道依赖性反应性。我们认为，T1D 通过改变负责控制氧化应激的关键细胞网络之间的平衡来损害脑血管的反应性，从而降低一氧化氮 (NO) 的生物利用度并产生 K+ 通道功能障碍。我们还有证据表明运动训练 (ExT) 可以恢复这种平衡。我们的中心假设是，T1D 改变了氧化细胞网络控制脑血管反应性的贡献，ExT 将通过影响这些细胞网络来减轻 T1D 期间的脑血管功能障碍。为了检验这一假设，提出以下目标。在具体目标#1中，我们将检验以下假设：NOS 和 K+ 通道在脑血管功能调节中的贡献在 T1D 中受损，而 ExT 将减轻/预防这种损害。在具体目标 #2 中，我们将检验以下假设：T1D 通过激活细胞网络损害脑血管的 NOS 和 K+ 通道依赖性反应，从而导致氧化应激增加，并且 ExT 可以通过影响这些关键网络来缓解脑血管功能障碍。在具体目标#3中，我们将测试以下假设：抗氧化途径的改变/操纵可能会导致 T1D 期间脑血管反应受损，而 ExT 可以通过影响这些抗氧化途径来减轻这种损害。在具体目标 #4 中，我们将检验 ExT 主要通过影响氧化应激来减少 T1D 期间脑缺血性脑损伤的假设。我们的研究将是首次全面综合的尝试，旨在研究 T1D 期间脑血管反应性受损的机制以及 ExT 对 T1D 期间脑血管和脑损伤的治疗益处。我们将使用现有技术来检查脑血管的体内反应性，并结合新的创新分子和生化方法来确定 T1D 和 ExT 对大脑的影响。公共卫生相关性：虽然 T1D 会导致包括中风在内的许多大脑疾病，但导致 T1D 对大脑影响的细胞机制实际上仍然未知。 ExT 可能是治疗 T1D 期间脑功能障碍的有效治疗方法，但是，没有研究检验这种方法是否可以治疗 T1D 期间脑血管功能障碍。我们的研究将首次检验 ExT 对 T1D 期间大脑功能的潜在治疗益处。