sGC oxidative stress controls cerebral blood flow and cognitive function

项目摘要 美国目前的人口趋势表明，与年龄相关的痴呆症正在成为一种严重的公众 健康危机。预计在不久的将来，其流行率和严重性将大幅增加。目前， 神经退行性疾病缺乏有效的治疗方法。因此，理解以下过程 为了设计有效和预防性的治疗措施，需要促进这些疾病的发生。 脑血流量的显著减少是导致脑血管疾病的主要血流动力学改变。 神经退行性变和与年龄相关的认知衰退。一氧化氮(NO)依赖的血管运动反应性 脑小动脉在调节脑血管血流动力学中起着中心作用 脑血流灌注。NO的大多数有益作用是通过其可溶性受体介导的 鸟苷酸环化酶(SGC)。NO/cGMP信号通路的增龄性下降是导致大鼠心脏功能受损的基础 为患有广泛神经退行性疾病的患者学习和处理新信息。 然而，在这些病例中，导致sGC失活的分子机制很少。 明白了。SGC结合的血红素的氧化或丢失导致NO-sGC功能的下降和 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，我们认为氧化导致sGC血红素的损失 负性影响脑血流量的调节，加重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来增强sGC功能- 独立的sGC激动剂应该防止/延缓与年龄相关的CBF和相关神经功能的下降， 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。将有两个具体目标：目标1将 确定sGC结合的血红素氧化状态的变化如何影响脑血流和认知功能 老化的小鼠。目标2将确定针对血红素和sGC的干预措施对年龄的影响。 脑内sGC功能的依赖性下降。我们的数据将提供经验证据，证明 SGC血红素的氧化还原状态是调节脑血流量所必需的，也是导致脑血流量下降的原因之一。 神经/认知功能。我们还旨在为以下原则提供证据：药理和 针对脑血管中血红素缺乏的sGC的饮食对策将缓解 神经退行性变，改善认知功能衰退。

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.