Microvascular mechanisms of neuroinflammation: role of Nrf2

神经炎症的微血管机制：Nrf2 的作用

• 批准号: 8748331
• 负责人: Anna Csiszar
• 金额: $ 30.34万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8748331
• 关键词: Age; Age-associated memory impairment; Aging; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Blood - brain barrier anatomy; Blood Vessels; Brain; Cells; Cerebrovascular Circulation; Cerebrum; Chronic; Cognitive; DNA; DNA Damage; DNA Repair Pathway; Data; Development; Disease; Elderly; Endothelial Cells; Engineering; Etiology; Extravasation; Functional disorder; Goals; Hypertension; Impaired cognition; Impairment; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Knowledge; Lead; Light; Microglia; Mission; Molecular Profiling; Mus; Neurons; Outcome; Oxidative Stress; Pathogenesis; Pathway interactions; Persons; Play; Prevention; Public Health; Quality of life; Relative (related person); Research; Risk Factors; Role; Serum; Societies; Testing; Up-Regulation; Vascular Cognitive Impairment; Vascular Dementia; Vent; Work; age related; aged; aging population; anti aging; attenuation; base; cytokine; disability burden; insight; mouse model; neuroinflammation; novel; novel therapeutic intervention; paracrine; prevent; programs; public health relevance; senescence; vascular inflammation

DESCRIPTION (provided by applicant): Age-related cognitive decline is a fundamental concern within the aging population and is the primary factor that leads to loss of independence. Although the specific mechanisms for age-related cognitive decline are not yet known, there is increasing evidence that age-related inflammatory changes play a crucial role. We and others have provided compelling initial evidence that age-related changes within the cerebrovasculature have a critical role in development of neuroinflammation. Our objective in this proposal is to determine the etiology of age- related pro-inflammatory changes within the cerebrovasculature. Nrf2, a master regulator of both endogenous cytoprotective and anti-inflammatory pathways, the central hypothesis of this application is that age-related endothelial Nrf2 dysfunction promotes cerebromicovascular inflammation and BBB disruption, which have a critical, direct role in chronic low-grade neuroinflammation and the etiology of age-related cognitive decline. We propose that Nrf2 can be manipulated pharmacologically, thus presenting a strong candidate target to pre- vent/reverse cerebromicrovascular impairment and vascular cognitive impairment in the elderly. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Determine the contribution of endothelial Nrf2 dysfunction to chronic low-grade cerebromicro-vascular inflammation in aged mice. Our hypothesis is that Nrf2 dysfunction leads to a pro-inflammatory shift in cytokine expression profile of endothelial cells in the cerebromicrovasculature of aged mice. 2) Determine the contribution of endothelial Nrf2 dysfunction to BBB disruption and perivascular microglia activation in aging. Our hypothesis is that age-related Nrf2 dysfunction promotes BBB disruption resulting in leakage of serum-derived factors to the brain parenchyma, which in turn indirectly exacerbates neuroinflammation by activating perivascular microglia. Increased neuroinflammation is expected to impact neuronal function. 3) Determine the extent to which Nrf2 dysfunction impacts initiation of senescence programs in cerebromicrovascular endothelial cells. We postulate, on the basis of preliminary data, that age-related Nrf2 dysfunction exacerbates oxidative stress, impairs DNA repair path- ways, and thereby increases DNA damage, triggering the execution of senescence program(s) in cerebro- microvascular endothelial cells. We predict that senescent endothelial cells exert pro-inflammatory, pro- oxidative effects on neighboring endothelial cells in a paracrine manner. Together, the proposed studies will identify a fundamental mechanism governing age-related exacerbation of cerebral microvascular inflammation eventually leading to neuronal circuit injury and cognitive impairment.

描述（由申请人提供）：与年龄相关的认知能力下降是老龄化人口中的一个基本问题，也是导致丧失独立性的主要因素。尽管与年龄相关的认知能力下降的具体机制尚不清楚，但越来越多的证据表明与年龄相关的炎症变化起着至关重要的作用。我们和其他人提供了令人信服的初步证据，表明脑血管内与年龄相关的变化在神经炎症的发展中起着关键作用。我们本提案的目的是确定脑血管内与年龄相关的促炎症变化的病因。 Nrf2 是内源性细胞保护和抗炎途径的主要调节因子，本申请的中心假设是，与年龄相关的内皮 Nrf2 功能障碍会促进脑血管炎症和 BBB 破坏，这在慢性低度神经炎症和与年龄相关的认知能力下降的病因学中具有关键、直接的作用。我们认为Nrf2可以通过药理学来操纵，从而为预防/逆转老年人的脑微血管损伤和血管认知障碍提供了强有力的候选靶点。在强有力的初步数据的指导下，这一假设将通过追求三个具体目标进行检验：1）确定内皮 Nrf2 功能障碍对老年小鼠慢性低度脑微血管炎症的影响。我们的假设是，Nrf2 功能障碍导致老年小鼠脑微血管系统内皮细胞细胞因子表达谱发生促炎性转变。 2) 确定衰老过程中内皮 Nrf2 功能障碍对 BBB 破坏和血管周围小胶质细胞激活的影响。我们的假设是，与年龄相关的 Nrf2 功能障碍会促进 BBB 破坏，导致血清衍生因子渗漏到脑实质，进而通过激活血管周围小胶质细胞间接加剧神经炎症。神经炎症的增加预计会影响神经元功能。 3)确定Nrf2功能障碍对脑微血管内皮细胞衰老程序启动的影响程度。根据初步数据，我们推测，与年龄相关的 Nrf2 功能障碍会加剧氧化应激，损害 DNA 修复途径，从而增加 DNA 损伤，触发脑微血管内皮细胞执行衰老程序。我们预测衰老的内皮细胞以旁分泌方式对邻近的内皮细胞发挥促炎、促氧化作用。总之，拟议的研究将确定控制与年龄相关的脑微血管炎症恶化的基本机制，最终导致神经元回路损伤和认知障碍。