The previous funding cycle of HL54131 focused on the role of survivin, a critical regulator of cell division and cell viability, in acute vascular injury. Fundamental discoveries were made that fulfilled the original specific aims, identifying survivin as a novel mediator of vascular smooth muscle cell (VSMC) proliferation, apoptosis and gene expression during pathologic vessel wall remodeling. These accomplishments spanned multiple fields of investigation, with identification of fundamental mechanisms of mitochondrial homeostasis, elucidation of new anti-apoptotic pathways in vascular injury, and 'translational'evaluation of novel molecular therapies of pathologic neointimal formation, in vivo. From these studies, a new paradigm emerged for the regulation of mitochondrial integrity, of pivotal importance for cell survival. We found that molecular chaperones of the Heat Shock Protein-90 (Hsp90) family accumulate in mitochondria, associate with component(s) of the permeability transition pore, notably Cyclophilin D (CypD), and antagonize its function 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 Hsp90 chaperones become upregulated, and are required to maintain VSMC viability, in vivo. Therefore, the hypothesis that mitochondrial Hsp90 chaperones are novel regulators of mitochondrial integrity and VSMC survival can be formulated, and will constitute the focus of the next funding cycle of HL54131. Experiments in the first specific aim will elucidate the subcellular trafficking, organelle import and molecular composition of a mitochondrial Hsp90 chaperone network in quiescent versus 'stressed'VSMC, exposed to hypoxia, or nutrient deprivation. The second specific aim will map the survival functions of mitochondrial Hsp90 chaperones in cultured VSMC, and in a novel transgenic mouse model of pathologic vascular remodeling, in vivo. The third specific aim will target the cytoprotective pathway of mitochondrial Hsp90 chaperones using a novel class of mitochondria-directed, small molecule Hsp90 inhibitors recently developed in our laboratory, i.e. Gamitrinibs. Experiments will test the effect of Gamitrinibs on mitochondrial integrity and cell death pathways in VSMC, as well as inhibition of neointimal formation in a wire-injury model, in vivo. In full continuity with the themes of HL54131 in its past funding cycles, the experimental plan combines mechanistic and translational studies of acute vascular injury. The results will elucidate a fundamental pathway of cell survival, and open new prospects for molecular therapy of pathologic vascular remodeling. RELEVANCE (See instructions): Despite improved knowledge of the pathogenesis of vascular injury, pathologic vessel wall remodeling remains a significant cause of morbidity, with limited therapeutic options. The elucidation and targeting of a novel, fundamental pathway of vascular smooth muscle cell survival centered on mitochondrial Hsp90 chaperones may provide novel therapeutic options to limit neointimal formation and pathologic vessel wall remodeling in humans.
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