The purpose of the research is to develop new therapeutic strategies and pharmacological agents for cancer, cardiac and liver diseases. To this end, the project focuses on mitochondria, which are key crossroads regulating cell death and survival pathways. Porin proteins of the outer membrane of mitochondria, specifically voltage dependent anion channels (VDAC), and their molecular partners are promising targets for drugs with directed action for prevention and treatment of a variety of diseases.
Creation of pharmacological agents with high selectivity and tissue specificity of therapeutic action requires a fundamental scientific understanding of mechanisms of regulation of mitochondrial porin proteins in pathological states of cells. The project is dedicated to this issues.
More specifically, the project is examining the role of porin proteins in cancer metabolism, cardiotoxicity, alcohol toxicity and hepatic encephalopathy in relation to endogenous mechanisms of VDAC regulation, interaction of VDAC with protein ligands, oxidative and calcium-dependent stress, activation of stress kinases, and phosphorylation of porin proteins and their molecular partners.
Identification of mechanisms regulating mitochondrial outer membrane permeability and the interactions of mitochondrial pores and channels with other proteins (e.g., Bax , Bak, tBid, tubulin) will allow development of new methods and strategies to suppress tumor cell resistance to anti-tumor substances and to protect hepatocytes and cardiomyocytes against alcohol toxicity, ischemia-reperfusion injury and other damaging stresses.
Investigators of the project will also identify and characterize signaling pathways whose activity underlies development of multicellular resistance and which can become targets for drug development to block drug resistance by tumor cells. The overall goal is to develop new therapeutic approaches to suppress tumor cell resistance to anticancer drugs, such as the anti-cancer protein TRAIL, by targeted effects on mitochondrial porin proteins and their molecular partners.
An additional objective of the project is to organize and conduct a theoretical and practical course on "Regulation of VDAC permeability and the role of mitochondrial porins in pathophysiology" for graduate students, young scientists and researchers of ITEB RAS and other scientific and medical institutions.