The role of PPARgamma-dependent communication pathways between brain endothelial cells and perivascular macrophages in immune-to-brain communication

全身性感染或炎症的发作促使先天免疫系统释放促炎细胞因子，这些细胞因子可以作用于大脑，启动一系列急性时相反应，包括激活下丘脑-垂体-肾上腺(HPA)轴。HPA功能的糖皮质激素介质起着关键的代谢和免疫调节作用，有助于应对眼前的威胁。Paul Sawchenko博士及其同事之前在该项目中的工作为负责免疫介导的HPA参与的神经血管回路定义了一个模型，该模型涉及脑血管内皮细胞(ECs)结合循环中的细胞因子(例如，IL-1；IL-1)，后者激活血管周围空间(血管周围细胞；PVCs)中的一种驻留巨噬细胞类型，以表现或增强环氧合酶(COX)的表达和前列腺素E2(PGE2)的释放。ECS也可能促进可诱导的前列腺素合成，而它们的这一能力受到PVCs的负面调节。聚氯乙烯和/或EC来源的PGE2随后以旁分泌方式刺激延髓中表达PGE2受体的儿茶酚胺神经元，并通过其已有文献记载的轴突投射，刺激表达促肾上腺皮质激素释放因子(CRF)的小细胞神经分泌神经元启动HPA输出。在这里，根据Sawchenko博士的建议，我建议进行实验，以进一步开发这一模型，测试其有效性/一般性，并探索从Sawchenko博士的工作中获得的干预中枢神经系统炎症性疾病的见解的治疗潜力。拟议的实验的一个重点将是参与依赖于PPARg的信号机制。

Episodes of systemic infection or inflammation engage the innate immune system to release pro-inflammatory cytokines that can act on the brain to initiate an array of acute phase responses, including activation of the hypothalamo-pituitary-adrenal (HPA) axis. Glucocorticoid mediators of HPA function serve critical metabolic and immunoregulatory roles that facilitate coping with the immediate threat. Previous work on this project by Dr. Paul Sawchenko and his colleagues has defined a model for a neurovascular circuit responsible for immune-mediated HPA engagement that involves binding of circulating cytokines (e.g., interleukin-1; IL-1) by cerebrovascular endothelial cells (ECs), which activate a resident macrophage cell type in the perivascular space (perivascular cells; PVCs) to manifest or enhance cyclooxygenase (COX) expression and prostaglandin E2 (PGE2) release. ECs may also contribute to inducible prostanoid synthesis, and their ability to do so is negatively regulated by PVCs. PGE2 of PVC and/or EC origin then acts in a paracrine fashion to stimulate catecholamine neurons in the medulla that express PGE2 receptors, and, by way of their well-documented axonal projections, parvocellular neurosecretory neurons that express corticotropin-releasing factor (CRF) to initiate HPA output. Here in accordance with Dr. Sawchenko I propose experiments to further develop this model, test its validity/generality and to explore the therapeutic potential of insights gleaned from Dr. Sawchenko's work for intervening in CNS inflammatory disease. One focus of the proposed experiments will be the involvement of peroxisome proliferator-activated receptor gamma (PPARg)-dependent signaling mechanisms.