PATHOGENIC MECHANISMS /THERAPEUTIC STRATEGIES /CELLULAR MODELS /mtDNA MUTATIONS

致病机制/治疗策略/细胞模型/线粒体DNA突变

基本信息

批准号：
7547770
负责人：
MERCY MASCREEN DAVIDSON
金额：
$ 24.91万
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/7547770
关键词：
Address Adrenal Cortex Hormones Animal Model Astrocytes Biological Models Blood - brain barrier anatomy Blood Vessels Brain Brain Neoplasms Carrier Proteins Cell membrane Cell model Cells Cerebral Edema Cerebral Infarction Cerebral cortex Clinical Coculture Techniques Collaborations Collagen Complement Complex Data Dexamethasone Disease Edema Electrical Resistance Endothelial Cells Event Fibrinogen Foot Process Functional disorder Funding Genes Glucocorticoids Goals Grant Hand Human Hydrocortisone In Vitro Ion Transport Lactate Transporter Lactic Acidosis Leucine-Specific tRNA Measures Methods Mitochondrial DNA Mitochondrial Diseases Mitochondrial Encephalomyopathies Modeling Mutation Myoblasts Neurodegenerative Disorders Neurons Outcome Pathogenesis Patients Permeability Physiological Point Mutation Proteins Reproducibility Research Personnel Respiratory Chain Side Standards of Weights and Measures Steroids Stroke System Technology Testing Therapeutic Tight Junctions Translations Umbilical vein Vascular Permeabilities Water analog aquaporin 4 cell type improved in vitro Model insight mitochondrial dysfunction mutant prevent programs therapeutic effectiveness tissue culture water channel

项目摘要

MELAS is the most common mitochondrial disease associated with a A3243G mutation in the tRNALeu gene of the mtDNA, and characterized by lactic acidosis, strokes, cerebral infarction and edema. The pathogenesis of strokes and edema in MELAS patients is not understood. Without a proper understanding of the pathophysiology, it has not been possible to devise rational therapies. Mitochondrial dysfunction in the cortical blood vessels may perhaps cause a breakdown of the blood-brain barrier (BBB). Using in vitro models of normal and MELAS BBB, we propose to study alterations in permeability functions, expression of tight junctions, water channels and lactate transporters, and correlate the data with respiratory chain function. We have the necessary wild-type and mutant cells, and we have demonstrated that we can construct the normal BBB with tight junctions. Management of stroke in MELAS patients with steroids has been anecdotally effective. Glucocorticoids are effective in treatment of cerebral edema associated with brain tumors. But the mechanism by which they act is not clear. The in vitro BBB system is a dynamic model which can be manipulated to test the effect of steroids in regulating brain water content. We propose to study the effect of hydrocortisone, and its synthetic analog, dexamethasone, on paracellular permeability, using the MELAS BBB model. First, these studies will provide insights into the physiological mechanisms associated with the BBB. Secondly, they will reveal critical information regarding pathological changes in vascular permeability in MELAS due to mitochondrial dysfunction and energy shortage. The culture model will also 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 therapeutic effectiveness of steroids in patients with this devastating illness.

MELAS是MTDNA的Trnaleu基因中与A3243G突变相关的最常见的线粒体疾病，其特征是乳酸性酸中毒，中风，脑梗塞和水肿。尚不清楚MELAS患者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，就不可能设计理性疗法。皮质血管中的线粒体功能障碍可能会导致血脑屏障（BBB）崩溃。使用正常和Melas BBB的体外模型，我们建议研究渗透率功能的改变，紧密连接的表达，水通道和乳酸转运蛋白，并将数据与呼吸链功能相关联。我们有必要的野生型和突变细胞，我们已经证明了我们可以用紧密连接构建正常的BBB。 Melas类固醇患者中风的管理至关重要。糖皮质激素可有效治疗与脑肿瘤相关的脑水肿。但是它们的作用机制尚不清楚。体外BBB系统是一个动态模型，可以操纵以测试类固醇在调节脑水含量中的影响。我们建议研究氢化可的松的作用及其合成类似物，地塞米松，使用Melas BBB模型在细胞细胞渗透性上。首先，这些研究将提供有关与BBB相关的生理机制的见解。其次，由于线粒体功能障碍和能量短缺，他们将揭示有关MELAS血管通透性的病理变化的关键信息。培养模型还将使我们能够评估导致渗透率增加的事件序列。最后，体外模型为测试这种毁灭性疾病患者的类固醇的治疗有效性提供了一种灵活的系统。