| Project
Description: |
The theme of this Program
Project application is to understand the signal transduction
pathways mediating cardioprotection using a multidisciplinary
approach that combines biophysics, physiology, proteomics and
genetics. Project 1 focuses on a central tenet of this theme, that
cardioprotective signaling converges on protection of mitohchondria
by preventing the mitochondrial permeability transition (MPT).
Project 1 will characterize the role of two distinct components
predisposing mitochondria to injury during anoxia/reoxygenation. The
MPT priming component is most relevant to the anoxic, or ischemic,
period and primes the mitochondria to undergo MPT during
reperfusion. The MPT priming component manifests as progressive MPT-independent
inner mitochondrial membrane (IMM) proton leak, matrix condensation
and remodeling, and cytochrome c mobilization and release and is
promoted by accumulation of long chain fatty acids (FA) and reactive
oxygen species (ROS). The MPT trigger component is most relevant to
the reoxygenation, or reperfusion, phase. Whether MPT occurs during
reperfusion is determined by the interplay between MPT inducers and
inhibitors present during rexoygenation (particularly matrix free Ca
levels and ROS) and electron transport capacity for regenerating
mitochondrial membrane potential (Dym),
which in turn depends on cytochrome c content and IMM proton leak. |
