The overall mission of Dr. Manfredi's research is to improve our understanding of mitochondrial encephalopathies by identifying and harnessing new mechanisms, such as cellular stress responses, that can be used to control the pathological events that occur in affected cells. For this project, he will focus on fundamental gaps in our understanding of the mitochondrial integrated stress response (mtISR), which has been associated with mitochondrial diseases and has been implicated as a potential pathogenic common denominator. Using a series of approaches, both established and technologically innovative, he will seek to generate a blueprint of the metabolic rewiring in the diseased central nervous system and identify targets potentially responsive to therapeutic modulation.