sGC oxidative stress controls cerebral blood flow and cognitive function

sGC氧化应激控制脑血流量和认知功能

• 批准号: 10373741
• 负责人: Iraida G. Sharina
• 金额: $ 42.9万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373741
• 关键词: Affect; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; American; Benchmarking; Binding; Blood Vessels; Brain; Bypass; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular system; Cognition; Cyclic GMP; Data; Dementia; Development; Disease; Functional disorder; Future; Health; Heart failure; Heme; Human; Impaired cognition; Impairment; Incidence; Intervention; Knowledge; Lead; Learning; Life; Measures; Mediating; Memory; Memory Loss; Metabolic; Metabolism; Mission; Molecular; Molecular Target; Mus; Nerve Degeneration; Nervous System Physiology; Neurodegenerative Disorders; Neurologic; Neurons; Nitric Oxide; Nitric Oxide Donors; Outcome; Oxidation-Reduction; Oxidative Stress; Oxides; Pathogenesis; Pathway interactions; Patients; Pharmacology; Play; Population; Prevalence; Preventive treatment; Process; Public Health; Pulmonary Hypertension; Regulation; Research; Role; Senile dementia; Severities; Signal Transduction; Soluble Guanylate Cyclase; Supplementation; Testing; Therapeutic Uses; United States National Institutes of Health; Vascular Dementia; Vascular Diseases; age group; age related; aging brain; arteriole; blood perfusion; blood pressure control; brain tissue; cerebral hemodynamics; cerebral oxygenation; cerebral vasomotor reactivity; cerebrovascular; cerebrovascular health; cognitive function; design; diet and exercise; dietary; effective therapy; hemodynamics; improved; iron oxide; negative affect; new therapeutic target; novel; novel therapeutics; oxidation; potential biomarker; prevent; protein degradation; receptor; side effect; targeted treatment; theories; therapeutic target; trend; vascular factor

Project Summary Current US demographic trend indicates that age-related dementia is becoming a serious public health crisis. Its prevalence and severity is expected to increase substantially in the near future. Currently, neurodegenerative diseases lack effective treatments. Therefore, understanding the processes that contribute to these diseases is needed for the design of effective and preventive treatment measures. Significant decrease in cerebral blood flow (CBF) is a major hemodynamic alteration leading to neurodegeneration and age-related cognitive decline. Nitric Oxide (NO)-dependent vasomotor reactivity of cerebral arterioles plays a central role in regulation of cerebrovascular hemodynamics and adequate brain blood perfusion. The majority of beneficial effects of NO are mediated via its receptor, soluble Guanylyl Cyclase (sGC). Age-dependent decline of NO/cGMP signaling underlies impaired ability of patients with a wide range of neurodegenerative diseases to learn and process new information. However, the molecular mechanisms contributing to sGC deactivation in these cases are poorly understood. Oxidation or loss of sGC-bound heme contributes to the decline of NO-sGC function and leads to sGC protein degradation. Our Preliminary data indicate that loss and oxidation of sGC heme is one of the factors associated with aging. We therefore propose that oxidation-induced loss of sGC heme negatively affects the regulation of CBF and exacerbate the decline of neurologic and cognitive functions with aging. Therefore, augmenting sGC function by supporting heme metabolism or applying heme- independent sGC activators should prevent/delay age-related decline in CBF and associated neurologic, memory, and cognitive functions. If proven, our hypothesis will stimulate the development of new therapeutics targeting cerebrovascular dysfunctions. There will be two Specific Aims: Aim 1 will determine how changes in oxidative state of sGC-bound heme affect CBF and cognitive functions in ageing mice. Aim 2 will establish the effect of heme- and sGC-targeting interventions on the age- dependent decline of sGC function in brain. Our data will provide empirical evidence that the integrity and redox state of sGC heme is essential for regulation of CBF and contributes to the decline of neurological/cognitive function. We also aim to provide proof for the principle that pharmacological and dietary countermeasures targeting heme-deficient sGC in cerebral vasculature will alleviate neurodegeneration and improve cognitive decline.

项目概要 当前美国的人口趋势表明，与年龄相关的痴呆症正在成为一个严重的公众问题 健康危机。预计其患病率和严重程度在不久的将来将大幅增加。现在， 神经退行性疾病缺乏有效的治疗方法。因此，了解这些过程 设计有效的预防性治疗措施需要对这些疾病做出贡献。 脑血流量（CBF）显着减少是导致血流动力学改变的主要因素 神经退行性变和与年龄相关的认知能力下降。一氧化氮 (NO) 依赖性血管舒缩反应性 脑小动脉的功能在调节脑血管血流动力学和充足的血流动力学方面发挥着核心作用。 脑血液灌注。 NO 的大部分有益作用是通过其受体（可溶性受体）介导的 鸟苷酸环化酶（sGC）。 NO/cGMP 信号的年龄依赖性衰退是细胞功能受损的基础 患有多种神经退行性疾病的患者学习和处理新信息。 然而，在这些情况下导致 sGC 失活的分子机制尚不清楚。 明白了。 sGC 结合血红素的氧化或丢失会导致 NO-sGC 功能的下降， 导致 sGC 蛋白降解。我们的初步数据表明 sGC 血红素的损失和氧化是 与衰老相关的因素之一。因此，我们认为氧化诱导的 sGC 血红素损失 对CBF的调节产生负面影响，加剧神经和认知功能的衰退 随着衰老。因此，通过支持血红素代谢或应用血红素来增强 sGC 功能 独立的 sGC 激活剂应预防/延缓与年龄相关的 CBF 和相关神经系统、 记忆和认知功能。如果得到证实，我们的假设将刺激新的开发 针对脑血管功能障碍的治疗。将有两个具体目标： 目标 1 将 确定 sGC 结合血红素氧化状态的变化如何影响 CBF 和认知功能 衰老的老鼠。目标 2 将确定血红素和 sGC 靶向干预措施对年龄的影响 大脑中 sGC 功能的依赖性下降。我们的数据将提供经验证据证明诚信 sGC 血红素的氧化还原状态对于 CBF 的调节至关重要，并有助于降低 神经/认知功能。我们还旨在为药理学和 针对脑血管系统中血红素缺乏的 sGC 的饮食对策将缓解 神经退行性变并改善认知能力下降。