Microvascular mechanisms of neuroinflammation: role of Nrf2

描述（由申请人提供）：老年人相关的认知能力下降是老龄化人群的一个基本问题，是导致丧失独立性的主要因素。虽然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。我们和其他人已经提供了令人信服的初步证据表明，年龄相关的变化在血管内的神经炎症的发展中起着关键作用。我们的目标是确定年龄相关的促炎性变化的病因学在血管内。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年龄相关的内皮Nrf2功能障碍促进血管微血管炎症和BBB破坏，这在慢性低度神经炎症和年龄相关的认知下降的病因学中具有关键的直接作用。我们认为Nrf2可以被调控，从而为预防/逆转老年人微血管损伤和血管性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，将通过追求三个具体目标来测试该假设：1）确定内皮Nrf2功能障碍对老年小鼠中慢性低度炎症微血管炎症的贡献。我们的假设是Nrf2功能障碍导致老年小鼠微血管内皮细胞的细胞因子表达谱发生促炎性变化。2)确定内皮Nrf2功能障碍对衰老中BBB破坏和血管周围小胶质细胞活化的贡献。我们的假设是，年龄相关的Nrf2功能障碍促进血脑屏障破坏，导致血清源性因子泄漏到脑实质，这反过来又通过激活血管周围小胶质细胞间接加剧神经炎症。预计神经炎症增加会影响神经元功能。3)确定Nrf2功能障碍影响微血管内皮细胞衰老程序启动的程度。基于初步数据，我们假设年龄相关的Nrf2功能障碍加剧氧化应激，损害DNA修复途径，从而增加DNA损伤，触发脑微血管内皮细胞衰老程序的执行。我们预测衰老内皮细胞以旁分泌方式对邻近内皮细胞产生促炎、促氧化作用。总之，拟议的研究将确定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。

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.