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Biochemical Basis of Axonal & Myelin Injury In Head Trauma

轴突的生化基础

基本信息

批准号：
7408535
负责人：
KEVIN Ka Wang WANG
金额：
$ 44.14万
依托单位：
BANYAN BIOMARKERS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-05-01 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7408535
关键词：
11-aminoundecanoic acid 2&apos ,3&apos -Cyclic-Nucleotide Phosphodiesterases Affect Affinity Amines Amyloid beta-Protein Precursor Animals Antibodies Antibody Specificity Antigens Arts Axon Binding Biochemical Biological Assay Biological Preservation Brain Brain Injuries Brain region C-terminal Calcium Calpain Carbon Carrier Proteins Caspase Cathepsins Cathepsins B Cell Adhesion Molecules Cell membrane Cerebrospinal Fluid Chemical Injury Chemicals Classification Coomassie blue Corpus Callosum Cortical Contusions Coupled Craniocerebral Trauma Craniotomy Cyclic Nucleotides Cysteine Cytoskeletal Proteins Cytoskeleton Data Databases Demyelinations Development Digestion Endopeptidases Ensure Enzyme Immunoassay Enzymes Event Future Gelatinase B Hippocampus (Brain)Homeostasis Hour Immunoassay Immunoblotting Immunoprecipitation In Vitro Injury Integral Membrane Protein Invasive Ischemic Brain Injury Keyhole Limpet Hemocyanin Knowledge Label Laboratories Length Link Mass Spectrum Analysis Matrix Metalloproteinases Mechanics Mediating Membrane Membrane Proteins Metalloproteases Methods Microglia Microtubules Myelin Myelin Associated Glycoprotein Myelin Basic Proteins Myelin Proteins Myelin Sheath N-terminal Nature Neurofilament-H Neurons Oligodendroglia Operative Surgical Procedures Oryctolagus cuniculus Parents Pathologic Pathology Pattern Peptide Hydrolases Peptides Plant Resins Precipitation Protease Inhibitor Proteins Proteolipids Proteolysis Proteolytic Processing Proteomics Rattus Relative (related person)Reporting Research Residual state Risk Running Sampling Sepharose Shapes Site Source Spectrin Staining method Stains Standards of Weights and Measures Structural Protein Structure System Techniques Technology Time Traumatic Brain Injury Tubulin base brain tissue carboxyl group caspase-3 caspase-6 caspase-7 cell type day design gel electrophoresis in vivo interest myelin degeneration neurofilament novel polyclonal antibody response to injury scale up tau Proteins therapy development tool white matter

项目摘要

DESCRIPTION (provided by applicant): A considerable amount of traumatic brain injury (TBI) research has focused on the pathologic significance of mechanical and chemical insults (e.g. disturbed calcium homeostasis) to the axons. Yet the precise biochemical mechanisms of axonal injury remain unclear. White matter loss and demyelination have been insufficiently studied in TBI, and we have little knowledge of the biochemical mechanisms of myelin damage. In the past, our laboratories and others have documented over-expression and activation of various proteases (e.g. calpains, caspases, and matrix metalloproteases) following brain injury. In this proposed research, we hypothesize that a subset of structural proteins in axons and myelin are differentially vulnerable to proteolysis after TBI. Inevitably, such proteolysis would result in degradation that significantly compromises the structural and functional integrity of axons and myelin sheaths leading to long-lasting axonal damage and demyelination. The proposed research represents the first systematic examination of the mechanisms of proteolvtic degradation of structural proteins in both axons and mvelin. Our preliminary data have already identified several axonally-enriched proteins that are vulnerable to proteolysis (neurofilament- H, and -L, microtubule-associated protein tau, axolemma-associated amyloid precursor protein [APR] and cytoskeletal proteins alphall- and (betaII-spectrin). Importantly, we have also identified at least two myelin proteins that are proteolysed after TBI (myelin basic protein [MBP] and myelin oligodendrocyte specific protein [MOSP]). Unique in vivo cleavage sites in proteolysis-prone protein substrates will be identified with state-of-the- art proteomic techniques. This knowledge will then allow us to generate novel "fragment-specific" antibodies, which will be used to immunohistochemically examine the precise subcellular distribution of these proteolytic products. The same antibody tools will be used to configure enzyme-linked immunoassays (ELISAs) to quantify these axonal and myelin proteolytic products in both brain tissue and cerebrospinal fluid (CSF). The latter method, if successful, will provide a novel and minimally-invasive way of quantifying TBI-associated axonal and myelin damage. These advances in understanding the proteolvtic mechanisms underlying axonal and myelin pathology in TBI will greatly accelerate development of therapies preserving the structural and functional integrity of axons and myelin.

描述（由申请人提供）：大量的创伤性脑损伤（TBI）研究集中在机械和化学损伤（例如钙稳态紊乱）对轴突的病理意义上。然而，轴突损伤的确切生化机制仍不清楚。白色物质丢失和脱髓鞘在TBI中的研究不够，我们对髓鞘损伤的生化机制知之甚少。过去，我们的实验室和其他实验室已经记录了脑损伤后各种蛋白酶（例如钙蛋白酶、半胱天冬酶和基质金属蛋白酶）的过度表达和活化。在这项研究中，我们假设轴突和髓鞘中的结构蛋白的一个子集在TBI后对蛋白水解有不同的脆弱性。不可避免地，这种蛋白水解将导致降解，这显著损害轴突和髓鞘的结构和功能完整性，导致持久的轴突损伤和脱髓鞘。这项研究首次系统地研究了轴突和mvelin中结构蛋白的蛋白水解降解机制。我们的初步数据已经确定了几个轴突富集的蛋白质是容易蛋白水解（神经丝- H，和-L，微管相关的蛋白tau，轴膜相关的淀粉样前体蛋白[APR]和细胞骨架蛋白β-和（β II-血影蛋白）。重要的是，我们还鉴定了至少两种在TBI后蛋白水解的髓鞘蛋白（髓鞘碱性蛋白[MBP]和髓鞘少突胶质细胞特异性蛋白[MOSP]）。独特的在体内切割位点的蛋白质水解倾向的蛋白质底物将确定与国家的最先进的蛋白质组学技术。这些知识将使我们能够产生新的“片段特异性”抗体，这些抗体将用于化学分析这些蛋白水解产物的精确亚细胞分布。相同的抗体工具将用于配置酶联免疫测定（ELISA），以定量脑组织和脑脊液（CSF）中的这些轴突和髓鞘蛋白水解产物。后一种方法，如果成功，将提供一种新的和微创的方式量化TBI相关的轴突和髓鞘损伤。在理解TBI中轴突和髓鞘病理学的蛋白水解机制方面的这些进展将大大加速保留轴突和髓鞘的结构和功能完整性的疗法的开发。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Neuronal and glial markers are differently associated with computed tomography findings and outcome in patients with severe traumatic brain injury: a case control study.

DOI：
10.1186/cc10286
发表时间：
2011-06-24
期刊：
Critical care (London, England)
影响因子：
0
作者：
Mondello S;Papa L;Buki A;Bullock MR;Czeiter E;Tortella FC;Wang KK;Hayes RL
通讯作者：
Hayes RL

Biomarkers of blast-induced neurotrauma: profiling molecular and cellular mechanisms of blast brain injury.

爆炸引起的神经创伤的生物标志物：分析爆炸脑损伤的分子和细胞机制。

DOI：
10.1089/neu.2008.0609
发表时间：
2009
期刊：
Journal of neurotrauma
影响因子：
4.2
作者：
Svetlov,StanislavI;Larner,StephenF;Kirk,DanielR;Atkinson,Joseph;Hayes,RonaldL;Wang,KevinKW
通讯作者：
Wang,KevinKW

Human traumatic brain injury induces autoantibody response against glial fibrillary acidic protein and its breakdown products.

人类创伤性脑损伤诱导针对神经胶质纤维酸性蛋白及其分解产物的自身抗体反应。

DOI：
10.1371/journal.pone.0092698
发表时间：
2014
期刊：
PloS one
影响因子：
3.7
作者：
Zhang Z;Zoltewicz JS;Mondello S;Newsom KJ;Yang Z;Yang B;Kobeissy F;Guingab J;Glushakova O;Robicsek S;Heaton S;Buki A;Hannay J;Gold MS;Rubenstein R;Lu XC;Dave JR;Schmid K;Tortella F;Robertson CS;Wang KK
通讯作者：
Wang KK

Acute NMDA toxicity in cultured rat cerebellar granule neurons is accompanied by autophagy induction and late onset autophagic cell death phenotype.