"PATHOGENIC MECHANISMS AND THERAPUETIC STRATEGIES IN MELAS"

“MELAS 的致病机制和治疗策略”

基本信息

批准号：
8445410
负责人：
MERCY MASCREEN DAVIDSON
金额：
$ 27.41万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8445410
关键词：
Address Adherens Junction Animal Model Astrocytes Autopsy Biochemical Biological Assay Blood - brain barrier anatomy Blood Vessels Brain Capillary Endothelial Cell Cell Culture Techniques Cells Cerebral Edema Cerebral Infarction Chemicals Coculture Techniques Collaborations Collagen Data Defect Diffusion weighted imaging Disease Edema Electrical Resistance Endothelial Cells Etiology Event Functional disorder Funding Genes Goals Human Hydrocortisone Immunoblotting In Vitro Inflammatory Intercellular Junctions Interferons Inulin Ions Laboratories Lactate Transporter Lactic Acidosis Lead Leucine-Specific tRNA Measurement Measures Mediating Membrane Mental Retardation Methods Micropore Filters Mitochondria Mitochondrial DNA Mitochondrial Diseases Mitochondrial Encephalomyopathies Modeling Molecular Mutation Pathogenesis Patients Permeability Pharmaceutical Preparations Physiology Play Point Mutation Process Protective Agents Proteins Regulation Relative (related person)Reporting Research Personnel Respiratory Chain Role Side Steroids Stroke Sucrose System Testing Therapeutic Therapeutic Agents Therapeutic Intervention Tight Junctions Tissues Translating Vascular Permeabilities Water Work base bench to bedside brain tissue cadherin 5 fetal fighting flexibility follow-up glycerylphosphoinositol immunocytochemistry in vitro Model in vivo insight mind control mitochondrial DNA mutation mitochondrial dysfunction occludin programs solute therapeutic target time interval tissue culture water channel

项目摘要

MELAS, a common mitochondrial disease associated with a m!3243A>G mutation in the tRNALeu(UUR) gene of the mitochondrial DNA, is characterized by strokes, lactic acidosis, cerebral infarction and edema. The pathogenesis of strokes and edema in MELAS is not understood. Without a proper understanding of the pathophysiology, it has not been possible to devise rational therapies for this devastating disease. Our hypothesis is that mitochondrial dysfunction in the cortical blood vessels causes a breakdown of the blood-brain barrier (BBB) leading to strokes and associated edema. We have successfully constructed a working in vitro model of a normal and MELAS BBB. We propose to study the function of the BBB in MELAS in this model. Specifically, we will analyze tight junction proteins that regulate BBB permeability, water channels, and lactate transporters and correlate our results with respiratory chain function. These in vitro studies at the cellular level will be extended to MELAS brain sections to compare and confirm our findings at the tissue level. Therapeutic management of MELAS is anecdotal and generally ineffective. Our in vitro model is a dynamic system that can be manipulated to test various BBB protective drugs, which can restore barrier function and thus can be useful therapeutic agents for strokes, lactic acidosis, and associated edema. We will use this model to test the effect of steroids in regulating water channels and of glycerphosphoinositol and interferon-b-1a in modulating the inflammatory process after strokes. First, these studies will provide insight into the physiology of the BBB. Secondly, they will reveal changes in vascular permeability in MELAS due to mitochondrial dysfunction and energy shortage. Third, the culture model will allow us to evaluate the sequence of events leading to the increase in permeability. Finally, the in vitro model provides a flexible system to test the therapeutic value of drugs to be used this devastating illness.

Melas是一种与M！3243a> g突变有关的一种常见线粒体疾病，其线粒体DNA的trnaleu（Uur）基因的特征是中风，乳酸酸中毒，大脑梗死和水肿。尚不清楚MELAS中风和水肿的发病机理。如果没有适当了解病理生理学的理解，就不可能为这种毁灭性疾病设计理性疗法。我们的假设是，皮质血管中的线粒体功能障碍会导致血脑屏障（BBB）的分解，导致中风和相关的水肿。我们已经成功构建了正常和Melas BBB的体外模型。我们建议在此模型中研究BBB在MELAS中的功能。具体而言，我们将分析调节BBB渗透率，水通道和乳酸转运蛋白的紧密连接蛋白，并将我们的结果与呼吸链功能相关联。这些在细胞水平的体外研究将扩展到Melas脑切片，以比较和确认我们在组织水平上的发现。 Melas的治疗管理是轶事，通常无效。我们的体外模型是一种动态系统，可以操纵以测试各种BBB保护药物，可以恢复屏障功能，因此可以作为中风，乳酸酸中毒和相关水肿的有用治疗剂。我们将使用该模型来测试类固醇在调节水通道，甘油磷酸肌醇和干扰素B-1A中的影响，以调节中风后调节炎症过程。首先，这些研究将洞悉BBB的生理学。其次，由于线粒体功能障碍和能量短缺，它们将揭示Melas血管通透性的变化。第三，培养模型将使我们能够评估导致渗透率增加的事件序列。最后，体外模型提供了一个灵活的系统，可以测试使用这种毁灭性疾病的药物的治疗价值。