"PATHOGENIC MECHANISMS AND THERAPUETIC STRATEGIES IN MELAS"

MELAS是一种与线粒体相关的常见线粒体疾病。线粒体DNA tRNALeu（UUR）基因3243A>G突变，以中风、乳酸性酸中毒、脑梗死和水肿为特征。MELAS中风和水肿的发病机制尚不清楚。没有对病理生理学的正确理解，就不可能设计出合理的治疗方法来治疗这种毁灭性的疾病。我们的假设是，皮质血管中的线粒体功能障碍导致血脑屏障（BBB）破裂，导致中风和相关水肿。我们成功构建了正常和MELAS血脑屏障的体外工作模型。我们建议在该模型中研究血脑屏障在MELAS中的功能。具体来说，我们将分析调节血脑屏障通透性、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联系起来。这些细胞水平的体外研究将扩展到MELAS脑切片，以比较和证实我们在组织水平上的发现。

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.