CAREER:Enabling transport across the blood-brain barrier by engineering thermodynamically favorable pathways

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CBET-1453312PI: Shikha NangiaThe blood-brain barrier serves the critical role of allowing only certain types of molecules to enter the brain from the blood stream. This important capability protects the brain from exposure to harmful chemical compounds. However, it also prevents certain drugs from entering the brain to treat brain disorders or diseases such as Alzheimer's disease. Since the segment of the US population older than 65 is expected to increase by 50% by 2030, and the cost of care to treat patients with these kinds of brain diseases is billions of dollars per year, finding new ways to help drugs cross the blood-brain barrier would provide significant benefits to patients and the nation. Nevertheless, understanding how therapeutic drug molecules move or don't move across the barrier into the brain has remained elusive. The proposed research will combine existing theories in a new way to understand how this movement is controlled across the blood-brain barrier, and will use an extensive computational tool-kit to engineer favorable pathways to transcend it. The proposed project will provide new molecular-level strategies to deliver drug molecules to the brain, and characterize the thermodynamics and transport kinetics of the blood-brain barrier. The focus will be to elucidate the molecular structure of the tight junction using a combination of molecular docking, analysis tools, and molecular dynamics. Additionally, the thermodynamics of the transport process properties of ions, water, and small drug molecules will be computed. The computed transport rates will be combined with stochastic simulation algorithm simulations to compute effective transport properties of drug across the tight junction strands. The education plan integrates findings from the research objectives with active-learning pedagogies to more effectively teach undergraduate and graduate thermodynamics courses.