Site-Specific Immune Control in the CNS

中枢神经系统中的位点特异性免疫控制

• 批准号: 6849706
• 负责人: LOIS ALTERMAN LAMPSON
• 金额: $ 19.33万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6849706
• 关键词: central nervous system; computer data analysis; experimental allergic encephalomyelitis; inhibitor /antagonist; interferon gamma; laboratory rat; neurochemistry; neuroimmunomodulation; neuropeptide receptor; neuropharmacology; neuroregulation; protein structure function; stainings; stimulant /agonist; substance P

DESCRIPTION (provided by applicant): We obtained evidence for 2 hypotheses: 1) Immune regulation in the brain is site-specific. 2) Local neurochemicals contribute to local control. This work has potentially important clinical implications: 1) It may help to explain the localization and the nature of some major neurologic disorders. 2) It may suggest a new approach to therapeutic control. The initial work was done in disease-free rats. We defined site-specific effects of locally-injected IFN-g. We showed that the injected IFN-g is influenced by local neurochemicals, including Substance P (SP). Now, we aim to show relevance in rats with ongoing CNS disease, using an EAE model. The project is being submitted as an R21 application in accordance with the R21 guidelines: 1) Site-specific immune control, and a role of local neurochemicals, could have major clinical implications, if we can show they are relevant during ongoing CNS disease. 2) Although we have extensive background data, we have do not yet have all the preliminary data that is needed for full-scale R01 support. If the experiments succeed, they will provide it. AIM. Define effect of SP manipulation in EAE and begin mechanistic studies. A. Confirm and extend pilot data showing SP manipulation can be protective (Methods, Exp. 1, 2). B. Show effects of SP manipulation are receptor-mediated, by appropriate receptors (Exp. 3, 4). C. Follow up selected findings, to set framework for, and begin, mechanistic studies (Exp. 5, 6). This is an amended application, revised in response to the reviewers' comments. Methods include intra-cerebral injection of cytokine (IFN-gamma) and pharmacological agents (SP, agonists, antagonists), antibody staining of tissue sections, and computer-assisted image analysis. Rats are used.

描述(申请人提供)：我们获得了两个假设的证据：1)大脑中的免疫调节是部位特异性的。2)局部神经化学物质有助于局部控制。这项工作具有潜在的重要临床意义：1)它可能有助于解释一些主要神经疾病的定位和性质。2)这可能为治疗控制提供一种新的途径。最初的工作是在无病大鼠身上进行的。我们定义了局部注射干扰素-g的特定部位效应。我们发现注射的干扰素-g受到局部神经化学物质的影响，包括P物质(SP)。现在，我们的目标是使用EAE模型来证明与正在进行的中枢神经系统疾病的大鼠的相关性。该项目是根据R21指南作为R21申请提交的：1)特定部位的免疫控制，以及局部神经化学物质的作用，如果我们能证明它们与正在进行的中枢神经系统疾病相关，可能会有重大的临床意义。2)虽然我们有广泛的背景数据，但我们还没有全面支持R01所需的所有初步数据。如果实验成功，他们将提供这种能力。瞄准。明确SP手法在EAE中的作用，并开始机理研究。A.确认并扩展试点数据，表明SP操作可以起到保护作用(方法、实验1、2)。B.SP操作的显示效果是由受体介导的，通过适当的受体(Exp。3、4)。C.跟进选定的研究结果，为机械论研究建立框架并开始(实验5、6)。这是一份修改后的申请表，根据评审员的意见进行了修改。方法包括脑内注射细胞因子(干扰素-γ)和药物(SP、激动剂、拮抗剂)、组织切片抗体染色和计算机辅助图像分析。用的是老鼠。