Identification of a protein that elicits immune-mediated neuronal dysfunction

鉴定引起免疫介导的神经元功能障碍的蛋白质

• 批准号: 7826951
• 负责人: Bonnie N Dittel
• 金额: $ 20.38万
• 依托单位: VERSITI WISCONSIN, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7826951
• 关键词: Activated Lymphocyte; Acute; Affect; Antigens; Area; Autoimmune Diseases; Automobile Driving; Axon; CD4 Positive T Lymphocytes; Cells; Central Nervous System Diseases; Cessation of life; Clinical; Defect; Demyelinations; Development; Disease; Encephalomyelitis; Experimental Autoimmune Encephalomyelitis; Exploratory/Developmental Grant; Family; Functional disorder; Glutamates; Goals; Growth Factor; Immune; Immune response; Immune system; Inflammation; Inflammatory Response; Knowledge; Link; Location; Lymphocyte; Mediating; Microtubules; Multiple Sclerosis; Names; Nervous system structure; Neuraxis; Neurodegenerative Disorders; Neuronal Dysfunction; Neuronal Injury; Neurons; Neurotransmitters; Nitric Oxide; Oligodendroglia; Optic Nerve; Pathogenesis; Proteins; Recovery; Reporting; Risk; Signal Pathway; Symptoms; T-Lymphocyte; TNF gene; Th1 Cells; Therapeutic; Tissues; Tubulin; Vision; cytokine; cytotoxic; disability; excitotoxicity; fast axonal transport; member; mouse model; nervous system disorder; new therapeutic target; novel; public health relevance; therapeutic target

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) a common disease of the central nervous system (CNS) with a direct link to immune system function. MS is characterized as an autoimmune disease, in which the immune system mounts an inappropriate immune response against the CNS. Specifically, self-reactive T lymphocytes are thought to drive disease pathogenesis by inducing an inflammatory response that results in plaque formation characterized by accumulations of immune cells in areas of demyelination. In addition to plaque formation, it has become clear that MS clinical symptoms also result from damage to neurons. Axonal loss has also been reported. A variety of immune-mediated mechanisms have been indicated in neuronal damage, but none have been specifically confirmed in MS. We have recently discovered that self-reactive T cells produce a secreted protein that induces neuronal injury by destabilization of microtubule -tubulin in axons. Axonal function and survival is dependent upon fast axonal transport of neurotransmitters and growth factors in the axons along microtubules. Thus the destablization of microtubules puts the neuron at risk for death. We have named this soluble factor Microtubule Axonal Destablizer or MAD. Using an experimental autoimmune encephalomyelitis (EAE) acute mouse model of MS, we have been able to demonstrate axonal dysfunction consistent with microtubule destablization in the CNS. This neuronal dysfunction was observed early in disease and was reversed upon recovery from EAE clinical disease. In order to further study the mechanisms of how MAD induces neuronal dysfunction, we need to purify and identify the MAD protein. This knowledge is required in order to determine if MAD or its signaling pathways can be targeted as a therapy for MS and other neurodegenerative diseases. Since MAD is an immune-mediated protein that directly affects neuronal function, its identification will facilitate our understanding of functional links between the immune and nervous systems. The hypothesis driving the current proposal is: Activated lymphocytes responding to CNS inflammation secrete a protein (MAD) that directly destabilizes axonal -tubulin causing a transport defect that directly results in MS clinical symptoms. The overall goal of this project is to determine whether MAD is a potential therapeutic target for MS or and other neurodegenerative disease. However, to ultimately achieve this goal, we must purify and identify MAD. This is the single aim of this application. PUBLIC HEALTH RELEVANCE: Many diseases of the nervous system, including multiple sclerosis, are often associated with damage to neurons resulting in disability. We have uncovered a novel mechanism whereby cells of the immune system directly mediate neuronal dysfunction. The goal of this proposal is to purify and identify the protein responsible for the neuronal damage such that it can be investigated as a new therapeutic target for the treatment of neurodegenerative diseases in subsequent studies.

描述（由申请人提供）：多发性硬化症（MS）一种与免疫系统功能直接联系的中枢神经系统（CNS）的常见疾病。 MS的特征是一种自身免疫性疾病，其中免疫系统对中枢神经系统的免疫反应不当。具体而言，认为自反应性T淋巴细胞被认为通过诱导炎症反应来促进疾病发病机理，从而导致斑块形成，其特征是脱髓鞘区域中免疫细胞的积累。除了形成牙菌斑外，很明显MS临床症状也造成神经元的损害。还报道了轴突损失。在神经元损伤中已经表明了多种免疫介导的机制，但在MS中没有明确证实。我们最近发现，自反应性T细胞产生一种分泌的蛋白质，该蛋白质通过轴突中微管 - 微管蛋白的稳定而诱导神经元损伤。轴突功能和存活取决于神经递质的快速轴突转运和沿微管的轴突生长因子。因此，微管的破坏使神经元处于死亡的危险之中。我们已经命名了此可溶性因子微管轴突破坏者或MAD。使用MS的实验性自身免疫性脑脊髓炎（EAE）急性小鼠模型，我们能够证明与中枢神经系统中的微管破坏性一致的轴突功能障碍。这种神经元功能障碍在疾病早期观察到，并在从EAE临床疾病中恢复后逆转。为了进一步研究MAD如何诱导神经元功能障碍的机制，我们需要纯化和鉴定MAD蛋白质。为了确定MAD或其信号通路是否可以作为MS和其他神经退行性疾病的疗法，就需要这些知识。由于MAD是一种直接影响神经元功能的免疫介导的蛋白质，因此其鉴定将有助于我们对免疫系统和神经系统之间功能联系的理解。驱动当前建议的假设是：对CNS炎症反应的活化淋巴细胞分泌一种直接破坏轴突 - 微管蛋白的蛋白质（MAD），导致转运缺陷直接导致MS临床症状。该项目的总体目标是确定MAD是否是MS或其他神经退行性疾病的潜在治疗靶点。但是，为了最终实现这一目标，我们必须净化并确定疯狂。这是此应用程序的一个目标。公共卫生相关性：许多神经系统的疾病，包括多发性硬化症，通常与神经元损害有关，导致残疾。我们发现了一种新型机制，即免疫系统的细胞直接介导神经元功能障碍。该提案的目的是净化和识别负责神经元损伤的蛋白质，以便可以将其作为治疗神经退行性疾病的新治疗靶点。

项目成果

Lymphocytes with cytotoxic activity induce rapid microtubule axonal destabilization independently and before signs of neuronal death.

• DOI: 10.1042/an20120087
• 发表时间: 2013-02-06
• 期刊: ASN neuro
• 影响因子: 4.7
• 作者: Miller NM;Shriver LP;Bodiga VL;Ray A;Basu S;Ahuja R;Jana A;Pahan K;Dittel BN
• 通讯作者: Dittel BN