| Project
Description: |
Project 2 is designed to
address the central theme of the PPG by examining kinase-dependent
regulation of the mitochondrial permeability transition (MPT) pore
in ischemic injury and protection. Project 2 complements the effort
of Project 1 in characterizing signaling events that modulate
mitochondrial permeability transition (MPT). Project 2 will
delineate the molecular mechanism by which PKCe,
a well-established cardioprotective kinase, interacts with and
modifies key components of the MPT pore. The present studies are
built upon our previous findings that the two core elements of the
MPT pore, the outer membrane protein VDAC and the inner membrane
protein ANT, are members of the PKCe
sub-proteome at the mitochondria. These findings have been confirmed
by the observation of strong localization of VDAC and ANT to PKCe
immuno-complexes. Accordingly, Project 2 hypothesizes that PKCe
interacts with, and modulates, VDAC and ANT via phosphorylation and
that these post-translational modifications of VDAC and ANT impact
their pore-forming abilities in the setting of ischemic injury and
cardiac protection. These studies will define, for the first time,
the precise manner in which a cardioprotective kinase interacts with
the MPT pore components; will map endogenous phosphorylation sites
on VDAC and ANT in the normal myocardium and examine changes in
these modifications that occur in the setting of cardioprotection;
and will provide novel insights regarding how PKCe-VDAC-ANT
complexes may be regulated by the Bcl-2 family of proteins. |
