Complement protection and anaphylatoxins in neuroinflammation

神经炎症中的补体保护和过敏毒素

• 批准号: 7406829
• 负责人: BRIAN K MARTIN
• 金额: $ 19.23万
• 依托单位: IOWA CANCER RESEARCH FOUNDATION, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-03 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7406829
• 关键词: Affect; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Anaphylatoxins; Antibodies; Apoptosis; Astrocytosis; Autoimmune Diseases; Biological Models; Biology; Brain; Brain region; Cell Death; Cellular biology; Central Nervous System Diseases; Chelating Agents; Complement; Complement 2; Complement 3a; Complement 5a; Complement Activation; Complement component C1; Complex; Copper; Corpus Callosum; Cuprizone; Data; Demyelinations; Diet; Disease; Environment; Enzymes; Excision; Genetic; Human; Huntington Disease; Immune; Immune system; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Investigation; Lead; Lymphocyte; Mediating; Mediator of activation protein; Modeling; Multiple Sclerosis; Mus; Myelin; Neuraxis; Neuroglia; Neuropathy; Oligodendroglia; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Pick Disease of the Brain; Play; Process; Production; Proteins; Recombinant Proteins; Recombinants; Research; Role; Signal Transduction; Spinal Cord; Staging; System; Testing; Toxic effect; Transgenic Mice; Viral; biological systems; chemotherapy induced neuropathy; design; feeding; genetic regulatory protein; human disease; mouse crry protein; mouse model; nervous system disorder; neuroinflammation; novel; prevent; receptor; research study; therapeutic target

DESCRIPTION (provided by applicant): Inflammation in the central nervous system is often accompanied by complement activation and the complement system has been implicated in diverse disorders such as Alzheimer's disease, amyotrophic lateral sclerosis and multiple sclerosis. We have utilized the cuprizone model of demyelination-remyelination and show that complement is a negative factor during demyelination, however lack of an intact complement system significantly delays remyelination. There is decreased expression of the protective Crry protein during demyelination and a CNS specific soluble Crry protein completely inhibits demyelination. These results indicate that complement is active even in CNS diseases without antibody involvement (as is the case in the cuprizone model). In order to further delineate the role of complement in neuroinflammation we propose to test the following hypotheses: (1) The production of anaphylatoxin proteins plays a key role in demyelination through increased microglial activation, but these inflammatory proteins are required for microglial activation required for myelin clearance. Both C3a and C5a are produced during complement activation, yet it is very difficult to dissect the roles these proteins, either alone or in combination. We have generated novel viral constructs (adenoviral and lentiviral) for CNS delivery and we have mice with genetic deletions in the receptors for these proteins that we can use to test our hypothesis. (2) Loss of Crry expression creates an environment in the corpus callosum that facilitates complement activation; yet decreased complement activation leads to loss of myelin clearance and remyelination delay. Our preliminary data have shown significant loss of Crry protein in cuprizone-treated mice and CNS production of a soluble Crry protein prevents demyelination. Surprisingly, when cuprizone is removed from the diet sCrry transgenic mice undergo demyelination when they should be remyelinating. These data show that primary demyelination can be prevented, but there is an adverse affect on remyelination with complement blockade. We will use virally delivered soluble Crry protein to test the ability of the protein to alter local demyelination and remyelination in this system. Our studies will begin to uncover how disparate complement proteins interact in the CNS to mediate different effector functions, information that will be critical for understanding how and when complement might be a candidate therapeutic target in disease. There are a number of diseases that are characterized by complement activation in the CNS including Alzheimer's disease, amyotrophic lateral sclerosis and multiple sclerosis. We are using a mouse model of demyelination and remyelination to study the role of immune complement in the effector stage of disease. Our unique model also allows us to study the most critical aspect of myelin biology in the human, namely the remyelination process.

描述（由申请人提供）：中枢神经系统的炎症通常伴随补体激活，补体系统与多种疾病如阿尔茨海默病、肌萎缩性侧索硬化和多发性硬化有关。我们已经利用脱髓鞘-髓鞘再生的cuprizone模型，并表明在脱髓鞘过程中补体是一个负性因素，然而缺乏完整的补体系统显着延迟髓鞘再生。在脱髓鞘过程中，保护性Crry蛋白的表达降低，并且CNS特异性可溶性Crry蛋白完全抑制脱髓鞘。这些结果表明，即使在没有抗体参与的CNS疾病中，补体也是有活性的（如铜腙模型中的情况）。为了进一步阐明补体在神经炎症中的作用，我们提出测试以下假设：（1）过敏毒素蛋白的产生通过增加小胶质细胞活化在脱髓鞘中起关键作用，但这些炎症蛋白是髓鞘清除所需的小胶质细胞活化所必需的。C3 a和C5 a都是在补体激活过程中产生的，但很难单独或联合分析这些蛋白质的作用。我们已经产生了用于CNS递送的新型病毒构建体（腺病毒和慢病毒），并且我们有在这些蛋白质的受体中具有遗传缺失的小鼠，我们可以使用这些蛋白质来测试我们的假设。(2)Crry表达的丧失在胼胝体中产生促进补体激活的环境;然而补体激活的降低导致髓鞘清除的丧失和髓鞘再生延迟。我们的初步数据显示，在cuprizone处理的小鼠中Crry蛋白的显著损失，并且可溶性Crry蛋白的CNS产生防止脱髓鞘。令人惊讶的是，当从饮食中去除cuprizone时，sCrry转基因小鼠在它们应该再生髓鞘时经历脱髓鞘。这些数据表明，原发性脱髓鞘是可以预防的，但补体阻断对髓鞘再生有不利影响。我们将使用病毒递送的可溶性Crry蛋白来测试该蛋白改变该系统中局部脱髓鞘和髓鞘再生的能力。我们的研究将开始揭示不同的补体蛋白如何在CNS中相互作用以介导不同的效应子功能，这些信息对于理解补体如何以及何时可能成为疾病的候选治疗靶点至关重要。有许多疾病的特征在于CNS中的补体激活，包括阿尔茨海默病、肌萎缩性侧索硬化和多发性硬化。我们正在使用脱髓鞘和髓鞘再生的小鼠模型来研究免疫补体在疾病效应阶段的作用。我们独特的模型还使我们能够研究人类髓鞘生物学最关键的方面，即髓鞘再生过程。