Research Projects

Mitochondria play a crucial role in cellular function, and understanding mitochondrial protein dysregulation is essential for addressing disease states. Human voltage-dependent anion channels (VDAC) 1 and 2 are upregulated in different cancers, with VDAC1 being pro-apoptotic and VDAC2 being anti-apoptotic. However, their molecular differences hinder their use as targets for cancer treatments. This proposal aims to identify molecular constituents that demarcate the two major isoforms of VDAC in human mitochondria. The project will map the dynamics of molecular regulatory elements specific to VDAC1 and VDAC2, identify interacting protein elements controlling hVDAC-specific metabolite flux, calcium homeostasis, and apoptosis, and design large-scale libraries of peptidomimetics designed to selectively target each isoform. The most potent peptidomimetics will be optimized to trigger mitoptosis under induced cellular stress conditions. In vivo delivery and outcome of the interaction of VDACs with these peptidomimetics will be developed as promising candidates for peptide-based therapeutics of cancer. The project's findings will contribute to our understanding of the mechanism and energetics regulating human mitochondrial VDAC1/2 function. The direct translational aspect of the project is the design, development, and refinement of biosimilars specific for each VDAC channel to curtailing cancer progression. Successful demonstration of peptidomimetics as drug candidates for VDACs could open similar therapeutic strategies for other debilitating human diseases.