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Complement protection and anaphylatoxins in neuroinflammation

神经炎症中的补体保护和过敏毒素

基本信息

批准号：
7911418
负责人：
BRIAN K MARTIN
金额：
$ 4.83万
依托单位：
IOWA CANCER RESEARCH FOUNDATION, INC.
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-03 至 2009-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7911418
关键词：
Alzheimer&apos 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 Response Investigation Lead Lymphocyte Mediating Mediator of activation protein Modeling Multiple Sclerosis Mus Myelin Neuraxis Neuroglia Neuropathy Oligodendroglia Pathology Pathway interactions Patients Pharmaceutical Preparations Pick Disease of the Brain Play Process Production Proteins Recombinants Research Role Signal Transduction Spinal Cord System Testing Toxic effect 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

项目摘要

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 here show that complement is a negative factor during demyelination, however lack of an intact complement system significantly delays remyelination. In addition, there is decreased expression of the protective Crry protein, suggesting increased susceptiblity to complement activation. In support of this idea, 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, yet are also important for remyelination. Both C3a and C5a are produced during complement activation, yet it is very difficult to dissect the roles of these proteins, either alone or in combination. We have generated novel adenoviral constructs 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. Our preliminary data have shown significant loss of Crry protein in cuprizone-treated mice and CNS production of soluble Crry protein prevents demyelination. These data show that primary demyelination can be prevented, but the effect on remyelination is yet unknown. We will use adenovirally 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 different complement proteins interact in the CNS to mediate diverse effector functions. This information will be critical for understanding how and when complement might be a candidate therapeutic target in CNS disease.

中枢神经系统中的炎症通常伴随补体激活，并且补体激活可导致中枢神经系统炎症。补体系统与多种疾病有关，例如阿尔茨海默病、肌萎缩性侧索硬化症、侧索硬化和多发性硬化。我们已经利用脱髓鞘-髓鞘再生的铜腙模型在脱髓鞘过程中，补体是一个负性因素，然而缺乏完整的补体系统显著延迟髓鞘再生。此外，在细胞凋亡中，保护性Crry蛋白，表明对补体激活的易感性增加。为了支持这一想法， 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疾病中也是有活性的（如在铜腙模型中的情况）。在为了进一步阐明补体在神经炎症中的作用，我们建议测试以下内容假设：（1）过敏毒素蛋白质的产生在脱髓鞘中起关键作用，但也对髓鞘再生很重要C3 a和C5 a都是在补体激活过程中产生的，但它非常很难剖析这些蛋白质的作用，无论是单独还是组合。我们创造了新的腺病毒构建体，我们有这些蛋白质受体基因缺失的小鼠，可以用来检验我们的假设(2)Crry表达的缺失在胼胝体中创造了一个环境，促进补体激活我们的初步数据显示，在哺乳动物中， cuprizone处理的小鼠和CNS产生可溶性Crry蛋白防止脱髓鞘。这些数据表明原发性脱髓鞘可以预防，但对髓鞘再生的影响尚不清楚。我们将使用腺病毒递送的可溶性Crry蛋白来测试该蛋白改变局部脱髓鞘的能力和髓鞘再生。我们的研究将开始揭示不同的补体蛋白在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成为CNS疾病候选治疗靶点。