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.

项目摘要 目前美国的人口趋势表明，与年龄有关的痴呆症正在成为一个严重的公众 健康危机。预计在不久的将来，其流行率和严重程度将大幅增加。目前， 神经退行性疾病缺乏有效的治疗方法。因此，了解 因此，需要设计有效的预防性治疗措施。 脑血流量（CBF）的显著减少是导致脑缺血的主要血液动力学改变。 神经变性和年龄相关的认知能力下降。一氧化氮（NO）依赖性血管反应性 脑小动脉的血流动力学在脑血管血流动力学的调节中起着核心作用， 脑血流灌注NO的大多数有益作用是通过其受体介导的，可溶性的 鸟苷酰环化酶（sGC）。NO/cGMP信号转导的依赖性下降是神经细胞功能受损的基础。 患有各种神经退行性疾病的患者学习和处理新信息。 然而，在这些情况下有助于sGC失活的分子机制很差， 明白sGC结合血红素的氧化或丢失有助于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 与衰老有关的因素之一。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，并加剧神经和认知功能的下降 随着年龄的增长。因此，通过支持血红素代谢或应用血红素增强sGC功能， 独立sGC激活剂应该预防/延迟CBF和相关神经系统的年龄相关性下降， 记忆和认知功能。如果得到证实，我们的假设将刺激新的 针对脑血管功能障碍的治疗。有两个具体目标：目标1 确定sGC结合血红素的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靶向干预对年龄的影响， 脑中sGC功能的依赖性下降。我们的数据将提供经验证据， sGC血红素的氧化还原状态对于CBF的调节是必不可少的，并有助于降低 神经/认知功能。我们的目的还在于为药理学和 针对脑血管系统中血红素缺乏sGC的饮食对策将减轻 神经退化和改善认知能力下降。