Axonal Protection for Multiple Sclerosis

多发性硬化症的轴突保护

基本信息

批准号：
7229858
负责人：
Jonathan David Glass
金额：
$ 19.77万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-01 至 2009-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7229858
关键词：
AK 295 Acute Animal Model Animals Attenuated Axon Biological Assay Blood Blood - brain barrier anatomy Brain Calcium Calpain Cells Choline Chronic Clinical Complement Craniocerebral Trauma Cytoskeleton Data Disease Dose Effectiveness Elevation Encephalomyelitis Endopeptidases Experimental Autoimmune Encephalomyelitis Experimental Models Glass Image Immune Immune Sera Immunoblotting Immunotherapeutic agent In Vitro Inflammatory Laboratories Libraries Measures Mediating Methods Modeling Modification Multiple Sclerosis Mus Myelin Neuraxis Neurologic Neurological Models Neurons Nucleosides Nucleotides Outcome Pathogenesis Pathologic Processes Pathology Patients Peptide Hydrolases Peripheral Nervous System Diseases Permeability Pharmaceutical Preparations Play Publishing Research Research Personnel Role Severities Severity of illness Signs and Symptoms Spectrin Spinal Cord Stroke Structure System Testing Tissues Western Blotting attenuation base calpain inhibitor disability disabling disease experience immunocytochemistry improved innovation killings mouse model nervous system disorder neurofilament neuroimaging novel novel strategies plaque lesion prevent programs

项目摘要

DESCRIPTION (provided by applicant): Multiple Sclerosis (MS) is a common neurological disorder characterized by immune attack on myelin and mylein forming cells of the central nervous system. Current treatments are directed at reducing the immune-mediated inflammatory damage to myelin. Recent observations from neuroimaging and pathological research demonstrate, however, that axonal pathology may also play a large role in the clinical deficits of MS patients, suggesting that the protection of axons may be a potentially important addition to MS therapies. The long-term objective of this proposal is to test the hypothesis that the protection of axons through the inhibition of calcium-activated proteases, or calpains, will ameliorate the clinical deficits in a mouse model of MS. This hypothesis is based on a large volume of data demonstrating the importance of calpain activation in axonal degeneration, and our published experience with preventing axonal degeneration and clinical disease in another animal model of neurological disease. In Aim 1 we will use the model of experimental autoimmune encephalomyelitis (EAE) to investigate the relationship of calpain activation to axonal degeneration and clinical disease. We will measured calpain activation using calpain activity assays and immunocytochemical and immunoblot methods to identify calpain-specific spectrin-breakdown products in tissues. In Aim 2 we will treat animals with EAE with our novel ketoamide calpain inhibitor AK295 and measure attenuation of disease by clinical and patholgical methods. In Aim 3 we will test the ability of AK295 to cross the blood-brain barrier (BBB), since any effective calpain inhibitor will need to get into the brain in sufficient quantities. We will also test the BBB permeability of 10 other novel calpain inhibitor compounds taken from our library of compounds, and compare them to AK295 for BBB permeability. Finally, we will attempt to increase BBB permeability by chemically modifying AK295 and other promising compounds by adding choline and nucleosides in order to take advantage of the inherent BBB transporter systems. These studies of calpain inhibition in a model of MS represent a novel approach to the treatment of this common and devastating neurological disorder. Combined with immunomodulatory therapy, axonal protection by calpain inhibition may significantly change the course of disease for people with MS.

描述（由申请人提供）：多发性硬化症（MS）是一种常见的神经系统疾病，其特征是对中枢神经系统的髓磷脂和肌蛋白质形成细胞的免疫攻击。当前的治疗方法旨在减少免疫介导的骨髓蛋白炎症损伤。然而，来自神经影像学和病理研究的最新观察结果表明，轴突病理学在MS患者的临床缺陷中也可能起着很大的作用，这表明轴突的保护可能是MS疗法的潜在重要补充。该提案的长期目标是检验以下假设：轴突通过抑制钙激活的蛋白酶或CALPAIN的保护将改善MS小鼠模型中的临床缺陷。该假设基于大量数据，证明了轴突变性中钙蛋白酶激活的重要性，以及我们在另一种神经系统疾病的动物模型中预防轴突变性和临床疾病的发表经验。在AIM 1中，我们将使用实验性自身免疫性脑脊髓炎（EAE）的模型来研究钙蛋白酶激活与轴突变性与临床疾病的关系。我们将使用钙蛋白酶活性测定和免疫细胞化学和免疫印迹方法测量钙蛋白酶的激活，以鉴定组织中钙蛋白酶特异性的谱蛋白破坏产物。在AIM 2中，我们将使用新型的酮酰胺钙蛋白酶抑制剂AK295治疗动物，并通过临床和病态方法测量疾病的衰减。在AIM 3中，我们将测试AK295越过血脑屏障（BBB）的能力，因为任何有效的钙蛋白酶抑制剂都需要足够数量进入大脑。我们还将测试从我们的化合物库中获取的其他10种新型Calpain抑制剂化合物的BBB渗透性，并将它们与AK295进行比较，以获得BBB的渗透性。最后，我们将尝试通过化学修饰AK295和其他有希望的化合物来提高BBB的渗透率，从而通过添加胆碱和核苷，以利用固有的BBB转运蛋白系统。这些在MS模型中对钙蛋白酶抑制作用的研究代表了治疗这种常见和毁灭性神经系统疾病的一种新方法。结合免疫调节疗法，通过钙蛋白酶抑制作用可以显着改变MS患者的疾病进程。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Long term monitoring of seizure patients.

对癫痫患者进行长期监测。

DOI：
发表时间：
1981
期刊：
Connecticut medicine
影响因子：
0
作者：
Holmes,GL;McKeever,M;Russman,BS
通讯作者：
Russman,BS

Peptidyl alpha-ketoamides with nucleobases, methylpiperazine, and dimethylaminoalkyl substituents as calpain inhibitors.

DOI：
10.1021/jm901221v
发表时间：
2010-09-09
期刊：
Journal of medicinal chemistry
影响因子：
7.3
作者：
Ovat A;Li ZZ;Hampton CY;Asress SA;Fernández FM;Glass JD;Powers JC
通讯作者：
Powers JC

Cocrystal structures of primed side-extending alpha-ketoamide inhibitors reveal novel calpain-inhibitor aromatic interactions.

DOI：
10.1021/jm800045t
发表时间：
2008-09-11
期刊：
JOURNAL OF MEDICINAL CHEMISTRY
影响因子：
7.3
作者：
Qian, Jin;Cuerrier, Dominic;Davies, Peter L.;Li, Zhaozhao;Powers, James C.;Campbell, Robert L.
通讯作者：
Campbell, Robert L.

Prolonged EEG and videotape monitoring in children.

对儿童进行长期脑电图和录像监测。