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使先天免疫系统参与释放促炎细胞因子，其可作用于大脑以启动一系列急性期反应，包括下丘脑-垂体-肾上腺（HPA）轴的激活。HPA功能的糖皮质激素介导剂发挥关键的代谢和免疫调节作用，促进应对眼前的威胁。Paul Sawchenko博士和他的同事在该项目上的先前工作已经定义了负责免疫介导的HPA参与的神经血管回路的模型，该模型涉及循环细胞因子的结合（例如，白细胞介素-1; IL-1），其激活血管周围空间中的驻留巨噬细胞类型（血管周围细胞; PVC）以表现或增强环氧合酶（考克斯）表达和前列腺素E2（PGE 2）释放。内皮细胞也可能有助于诱导型前列腺素类合成，并且它们这样做的能力受到PVC的负调控。PVC和/或EC来源的PGE 2然后以旁分泌方式起作用，以刺激表达PGE 2受体的髓质中的儿茶酚胺神经元，并且通过其充分记录的轴突投射，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，以启动HPA输出。在这里，根据Sawchenko博士的建议，我提出了进一步开发该模型的实验，测试其有效性/通用性，并探索从Sawchenko博士的工作中收集的见解的治疗潜力，用于干预CNS炎症性疾病。拟议的实验的一个重点将是过氧化物酶体增殖物激活受体γ（PPARg）依赖的信号传导机制的参与。

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.