PATHOGENIC MECHANISMS /THERAPEUTIC STRATEGIES /CELLULAR MODELS /mtDNA MUTATIONS

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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.