C-reactive Protein, Autoimmunity, and Inflammation in the Central Nervous System

C 反应蛋白、自身免疫和中枢神经系统炎症

• 批准号: 8725995
• 负责人: Tyler T Wright
• 金额: $ 3.15万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8725995
• 关键词: Acute-Phase Proteins; Address; Affect; Animal Model; Antigens; Autoimmune Process; Autoimmunity; Automobile Driving; Binding; Biological; Biology; Blood; Bone Marrow; C-reactive protein; CD4 Positive T Lymphocytes; Cells; Central Nervous System Diseases; Clinical; Coculture Techniques; Committee Members; Data; Demyelinations; Dendritic Cells; Development; Disease; Effector Cell; Experimental Autoimmune Encephalomyelitis; Fatigue; Genotype; Goals; Hepatic; Human; Immune system; In Vitro; Individual; Infiltration; Inflammation; Inflammatory; Injection of therapeutic agent; Knowledge; Link; Literature; Maps; Mediating; Medical; Mentors; Mouse Strains; Multiple Sclerosis; Mus; Myelin; Natural Immunity; Nerve Degeneration; Nervous system structure; Neuraxis; Neurologic; Neurons; Outcome; Paralysed; Pathogenesis; Pathway interactions; Patients; Peptides; Phenotype; Productivity; Protein Binding; Publishing; Quality of life; Relapse; Research; Research Project Grants; Rodent Model; Role; Severities; Source; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic; Time; Transgenes; Transgenic Organisms; Treatment Cost; Tremor; United States; Work; adaptive immunity; base; career; cell type; cytokine; disorder prevention; effective therapy; forging; in vivo; insight; interferon therapy; neuroimmunology; novel; novel therapeutics; oligodendrocyte-myelin glycoprotein; prevent; promoter; protective effect; protein expression; public health relevance; receptor; research study; response; white matter

DESCRIPTION (provided by applicant): Human C-reactive protein is an acute phase protein whose blood concentrations rise dramatically in response to inflammatory insults. Though CRP is primarily of hepatic origin, it is also produced by neurons during times of CNS inflammation. CRP's contribution to CNS inflammation and the biological importance of neuronal CRP are unknown. Published work from our lab shows that mice containing the human CRP transgene (CRPtg) are protected from myelin oligodendrocyte glycoprotein (MOG) peptide induced experimental autoimmune encephalomyelitis (EAE), a rodent model of Multiple Sclerosis (MS). Human CRP, expressed transgenically or administered by injection, delays onset and reduces severity of EAE, and these effects rely on expression of Fc?RIIB. We showed that transgenic or injected human CRP is unable to ameliorate EAE in Fc?RIIB-/- mice. The Fc?RIIB-expressing cell that responds to human CRP remains unknown. The goals of this research project are (1) to determine the Fc?RIIB expressing cell through which CRP exerts protection against EAE and (2) to determine if CNS specific expression of human CRP is sufficient to protect mice from EAE. I hypothesize that CRP mediated amelioration of EAE is manifest via CRP binding to Fc?RIIB on dendritic cells (DCs), and that local CNS expression of CRP is sufficient to achieve this benefit. Utilizing purified human CRP, I will analyze bone marrow derived DCs from mice either sufficient or deficient for Fc?RIIB to determine if CRP alters their activation status in viro and if any CRP driven effect depends upon Fc?RIIB. Since EAE/MS is considered to be a T cell mediated disease, I will examine CRP's effect on DCs' ability to stimulate T cell proliferation and polarization in vitro in DC:T cell co-cultures using wildtype versus Fc?RIIB deficient DCs as antigen (MOG) presenting cells. I will also induce EAE in humanized mice (mice that express human CRP and express human Fc?RIIB exclusively on DCs, but no mouse Fc?RIIB) to investigate if the Fc?RIIB->DC axis is sufficient for CRP mediated amelioration of EAE. To assess the requirement of DCs, I will induce EAE in CRPtg in which DCs have been selectively depleted. Finally, using mice wherein human CRP expression is limited to neurons I will determine if exclusively CNS expression of human CRP is sufficient to protect mice from EAE. I will induce EAE in nCRPtg and compare their disease to CRPtg and WT mice. Successful pursuit of the work described herein will identify the effector cell by which CRP exerts protection in EAE, confirm that a human CRP->human Fc?RIIB axis operates in vivo, and elucidate the source of protective CRP. This will pave the way for development of new therapies that will benefit the ~350,000 U.S. citizens with MS.

描述（由申请人提供）：人C反应蛋白是一种急性期蛋白，其血药浓度响应于炎症损伤而显著升高。虽然CRP主要是肝脏来源，但在CNS炎症期间也由神经元产生。CRP对CNS炎症的作用和神经元CRP的生物学重要性尚不清楚。我们实验室发表的工作表明，含有人CRP转基因（CRPtg）的小鼠受到保护，免受髓鞘少突胶质细胞糖蛋白（MOG）肽诱导的实验性自身免疫性脑脊髓炎（EAE），多发性硬化症（MS）的啮齿动物模型。人CRP，转基因表达或注射给药，延迟发病，降低EAE的严重程度，这些影响依赖于表达Fc？RIIB。我们发现，转基因或注射人CRP是无法改善EAE在Fc？RIIB-/-小鼠。FC？对人CRP有反应的RIIB表达细胞仍然未知。本研究的目的是（1）确定Fc？CRP通过表达RIIB的细胞发挥针对EAE的保护作用，以及（2）确定人CRP的CNS特异性表达是否足以保护小鼠免受EAE。我假设CRP介导的EAE改善是通过CRP与Fc结合来表现的？RIIB对树突状细胞（DC）的作用，并且CRP的局部CNS表达足以实现这种益处。利用纯化的人CRP，我将分析来自小鼠的骨髓来源的DC无论是足够或缺乏Fc？RIIB，以确定CRP是否改变其体内活化状态，以及是否有任何CRP驱动效应取决于Fc？RIIB。由于EAE/MS被认为是一种T细胞介导的疾病，我将研究CRP对DC刺激T细胞增殖能力的影响， 极化在体外DC：T细胞共培养使用野生型与Fc？RIIB缺陷型DC作为抗原（MOG）呈递细胞。我还将在人源化小鼠（表达人CRP和表达人Fc的小鼠）中诱导EAE。RIIB只对DC，但没有小鼠Fc？RIIB）调查，如果Fc？RIIB->DC轴足以用于CRP介导的EAE的改善。为了评估对DC的需求，我将在选择性耗尽DC的CRPtg中诱导EAE。最后，使用其中人CRP表达限于神经元的小鼠，我将确定人CRP的仅CNS表达是否足以保护小鼠免受EAE。我将在nCRPtg中诱导EAE，并将其疾病与CRPtg和WT小鼠进行比较。本文所述工作的成功进行将鉴定CRP发挥保护作用的效应细胞 在EAE中，证实人CRP->人Fc？RIIB轴在体内起作用，阐明保护性CRP的来源。这将为开发新的疗法铺平道路，这些疗法将使约35万美国MS患者受益。