Functional Anatomy of Neuroimmune Interactions

神经免疫相互作用的功能解剖学

• 批准号: 7640658
• 负责人: Paul E. Sawchenko
• 金额: $ 50.4万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-23 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7640658
• 关键词: Ablation; Acute; Acute-Phase Reaction; Adrenal Glands; Agonist; Anatomy; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Autoimmune Diseases; Binding; Biological Assay; Blood; Blood Vessels; Brain; Brain Stem; Catecholamines; Cell Nucleus; Cells; Cerebrum; Communication; Corticotropin-Releasing Hormone; Cytokine Signaling; Dinoprostone; Dose; Drug Delivery Systems; Elements; Endothelial Cells; Endotoxins; Fever; Genes; Glucocorticoids; Goals; Hypothalamic structure; Immediate-Early Genes; Immune; Immunologic Markers; Immunosuppressive Agents; Immunotoxins; Individual; Infection; Inflammation; Injury; Interleukin-1; Knockout Mice; Lesion; Limb structure; Lipopolysaccharides; Liposomes; Mediating; Mediator of activation protein; Meningeal; Methods; Microinjections; Modeling; Motor Activity; Mus; Mutant Strains Mice; Neurons; Nuclear; Output; PTGS2 gene; Participant; Pattern; Pericytes; Pharmaceutical Preparations; Phase; Pituitary Gland; Pituitary-Adrenal System; Play; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Rattus; Recruitment Activity; Regulation; Residual state; Role; Signaling Molecule; Site; Source; Specific qualifier value; Specificity; Stimulus; Techniques; Testing; Time; base; cell type; cytokine; feeding; immune function; macrophage; man; novel; paracrine; parvocellular; receptor; research study; response; retrograde transport

DESCRIPTION (provided by applicant): Cytokines, such as interleukin-1 (IL-1), released from activated immune cells during sickness or injury act on the brain to stimulate the hypothalamo-pituitary-adrenal (HPA) axis. A suggested model for this effect involves paracrine actions of prostaglandin E2 (PGE2), released from local perivascular cells as a result of IL-1 binding on brainstem catecholamine neurons that project to the hypothalamus for the initiation of HPA responses. Four sets of experiments will test this model, and advance the broader goal of clarifying the circuits and mechanism underlying immune-to-brain communication. First, to evaluate a posited interaction between endothelial and perivascular cells in transducing blood-borne cytokine signals and initiating PGE2 synthesis, the sensitivity of the two cell types in expressing inducible cyclooxygenase (COX-2) and other markers of immune activation will be compared in rats and mice over a range of IL-1 and endotoxin treatments, and the cell-specific expression of potential mediators will be examined. Knockout mice will be used to assess the roles of select genes in COX-2 induction and resultant HPA responses. Transcriptional profiling of endothelial and perivascular cells isolated from immune-stimulated mice will evaluate suspected participants in this interaction and identify novel ones. Second, a liposome-mediated targeting approach will be used to selectively destroy brain macrophages, including perivascular cells. The impact of this on HPA and other acute phase endpoints, and the CNS circuitry that mediates them, will be determined using Fos-based functional anatomical assays. Third, anatomical tracing combined with PGE2 receptor localization will identify receptor mechanisms and cell groups that participate in PGE2-mediated HPA activation. Local microinjections of subtype-selective drugs will assess the involvement of specific receptors in brainstem and other implicated sites of action. Finally, because disruption of catecholamine inputs to hypothalamus only partially mitigates endotoxin-induced HPA activation, combined lesioning, tracing and Fos-based methods will be used to identify additional candidate mediators of endotoxin effects on hypothalamus, and specify the conditions under which they are called into play. Glucocorticoid mediators of the HPA axis exert potent immunosuppressive and anti-inflammatory effects. Disruption of this restraining influence on immune function has been implicated in the genesis of autoimmune disease in animal models and in man.

描述(申请人提供)：细胞因子，如白介素1(IL-1)，在疾病或受伤时从激活的免疫细胞释放出来，作用于大脑，刺激下丘脑-垂体-肾上腺(HPA)轴。这一效应的一个建议模型涉及前列腺素E2(PGE2)的旁分泌作用，由于IL-1与脑干儿茶酚胺神经元结合，局部血管周围细胞释放前列腺素E2(PGE2)，儿茶酚胺神经元投射到下丘脑启动HPA反应。四组实验将测试这一模型，并提出更广泛的目标，即澄清免疫与大脑沟通的基础电路和机制。首先，为了评估内皮细胞和血管周围细胞在转导血源性细胞因子信号和启动PGE2合成方面的假设相互作用，将在一系列IL-1和内毒素治疗下比较大鼠和小鼠两种细胞类型表达诱导性环氧合酶(COX-2)和其他免疫激活标志的敏感性，并检测潜在介质的细胞特异性表达。基因敲除小鼠将被用来评估选择的基因在COX-2诱导和由此产生的HPA反应中的作用。从免疫刺激小鼠分离的血管内皮细胞和血管周围细胞的转录图谱将评估这种相互作用中的可疑参与者，并确定新的参与者。其次，将使用脂质体介导的靶向方法选择性地摧毁脑巨噬细胞，包括血管周围细胞。这对HPA和其他急性期终点的影响，以及调节它们的中枢神经系统回路，将使用基于Fos的功能解剖学分析来确定。第三，解剖示踪结合PGE2受体定位将确定参与PGE2介导的HPA激活的受体机制和细胞群。局部微量注射亚型选择性药物将评估脑干和其他相关作用部位的特定受体的参与。最后，由于干扰下丘脑的儿茶酚胺输入只能部分缓解内毒素诱导的HPA激活，因此将结合损伤、追踪和基于Fos的方法来确定内毒素对下丘脑影响的其他候选介质，并指定它们发挥作用的条件。HPA轴的糖皮质激素介质具有强大的免疫抑制和抗炎作用。在动物模型和人类中，这种对免疫功能的抑制影响的破坏与自身免疫性疾病的发生有关。