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

血脑屏障起着至关重要的作用，它只允许某些类型的分子从血液中进入大脑。这种重要的能力可以保护大脑免受有害化合物的影响。然而，它也阻止某些药物进入大脑，以治疗大脑紊乱或阿尔茨海默病等疾病。到2030年，美国65岁以上的人口预计将增加50%，而治疗这类脑部疾病患者的护理成本每年高达数十亿美元，因此，找到帮助药物通过血脑屏障的新方法将为患者和国家带来重大利益。然而，了解治疗药物分子如何移动或不移动穿过屏障进入大脑仍然是难以捉摸的。拟议的研究将以一种新的方式结合现有的理论来理解这种运动是如何通过血脑屏障控制的，并将使用广泛的计算工具包来设计有利的途径来超越它。该项目将提供新的分子水平策略，将药物分子输送到大脑，并表征血脑屏障的热力学和运输动力学。重点将是阐明紧密连接的分子结构使用分子对接，分析工具和分子动力学的组合。此外，离子，水和小药物分子的传递过程性质的热力学将被计算。计算的输运率将与随机模拟算法模拟相结合，以计算药物在紧密连接链上的有效输运特性。该教育计划将研究结果与主动学习教学法相结合，以更有效地教授本科生和研究生的热力学课程。

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.