The previous funding cycle of HL54131 focused on the role of survivin, a critical regulator of cell division andcell viability, in acute vascular injury. Fundamental discoveries were made that fulfilled the original specificaims, identifying survivin as a novel mediator of vascular smooth muscle cell (VSMC) proliferation,apoptosis and gene expression during pathologic vessel wall remodeling. These accomplishments spannedmultiple fields of investigation, with identification of fundamental mechanisms of mitochondrial homeostasis,elucidation of new anti-apoptotic pathways in vascular injury, and 'translational' evaluation of novelmolecular therapies of pathologic neointimal formation, in vivo. From these studies, a new paradigmemerged for the regulation of mitochondrial integrity, of pivotal importance for cell survival. We found thatmolecular chaperones of the Heat Shock Protein-90 (Hsp90) family accumulate in mitochondria, associatewith component(s) of the permeability transition pore, notably Cyclophilin D (CypD), and antagonize itsfunction via a protein folding mechanism that maintains mitochondrial integrity and blocks cell death.Recent experimental evidence shows that this pathway is operative in acute vascular injury, where Hsp90chaperones become upregulated, and are required to maintain VSMC viability, in vivo. Therefore, thehypothesis that mitochondrial Hsp90 chaperones are novel regulators of mitochondrial integrity and VSMCsurvival can be formulated, and will constitute the focus of the next funding cycle of HL54131. Experimentsin the first specific aim will elucidate the subcellular trafficking, organelle import and molecular compositionof a mitochondrial Hsp90 chaperone network in quiescent versus 'stressed' VSMC, exposed to hypoxia, ornutrient deprivation. The second specific aim will map the survival functions of mitochondrial Hsp90chaperones in cultured VSMC, and in a novel transgenic mouse model of pathologic vascular remodeling, invivo. The third specific aim will target the cytoprotective pathway of mitochondrial Hsp90 chaperones usinga novel class of mitochondria-directed, small molecule Hsp90 inhibitors recently developed in ourlaboratory, i.e. Gamitrinibs. Experiments will test the effect of Gamitrinibs on mitochondrial integrity and celldeath pathways in VSMC, as well as inhibition of neointimal formation in a wire-injury model, in vivo. In fullcontinuity with the themes of HL54131 in its past funding cycles, the experimental plan combinesmechanistic and translational studies of acute vascular injury. The results will elucidate a fundamentalpathway of cell survival, and open new prospects for molecular therapy of pathologic vascular remodeling.
Despite improved knowledge of the pathogenesis of vascular injury, pathologic vessel wall remodelingremains a significant cause of morbidity, with limited therapeutic options. The elucidation and targeting of anovel, fundamental pathway of vascular smooth muscle cell survival centered on mitochondrial Hsp90chaperones may provide novel therapeutic options to limit neointimal formation and pathologic vessel wallremodeling in humans.
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