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

职业：通过设计热力学有利的途径实现跨越血脑屏障的运输

• 批准号: 1453312
• 负责人: Shikha Nangia
• 金额: $ 50万
• 依托单位: Syracuse University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1453312&HistoricalAwards=false
• 关键词: CAREER; Enabling; transport; across; blood

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.

CBET-1453312PI：Shikha Nangiathe血脑屏障起着仅允许某些类型的分子从血流中进入大脑的关键作用。这种重要的能力可保护大脑免于暴露于有害化合物中。但是，它还阻止某些药物进入大脑以治疗脑部疾病或诸如阿尔茨海默氏病等疾病。由于预计到2030年的美国人口的细分市场预计将增加50％，而治疗此类脑部疾病的患者的护理费用为每年数十亿美元，因此寻找帮助跨越血脑屏障的药物的新方法将为患者和国家提供重大收益。 然而，了解治疗药物分子如何移动或不穿过障碍物进入大脑仍然难以捉摸。拟议的研究将以一种新的方式将现有理论结合在一起，以了解如何在血脑屏障中控制这种运动，并将使用广泛的计算工具套件来设计出良好的途径来超越它。拟议的项目将提供新的分子级策略，以向大脑传递药物分子，并表征血脑屏障的热力学和运输动力学。重点是使用分子对接，分析工具和分子动力学的组合来阐明紧密连接的分子结构。此外，将计算离子，水和小药物分子的传输过程特性的热力学。计算的运输速率将与随机模拟算法模拟结合使用，以计算在紧密连接链中药物的有效运输特性。该教育计划将研究目标与主动学习教学法结合起来，以更有效地教授本科和研究生热力学课程。