Multiscale Modeling of Transport though Blood Brain Barrier

生物制品的运输，包括抗体、酶、药物分子等，脑实质的损伤 由于血脑屏障（BBB）的存在，有效递送药物穿过BBB的关键策略是 将药物包裹在纳米载体/纳米细胞（NC）内，然后用生物活性肽功能化NC， 蛋白质或抗体，其受体在靶位点高度表达，导致受体介导的 主动运输。通过受体介导的转胞吞作用（RMT）有效递送NC是一种高度有效的方法。 复杂和多尺度的过程，这是很难调查通过特定规模的技术（两者） 实验上和数值上）。在这个项目中，我们建议建立一个跨学科的研究， 结合多尺度模型和体外细胞培养研究NCs的RMT 实验提出的研究目标是：（a）通过BBB建立RMT的多尺度模型， 该模型包括NC结合、内化和排出的中尺度随机模型， 在分子水平上用于特定蛋白质-蛋白质和蛋白质-脂质相互作用的原子模型;（B）验证我们的 通过比较多尺度模型与体外细胞培养实验对配体浓度的影响; 以及（c）探索颗粒尺寸、颗粒形状/类型、配体密度、配体类型以及 通过建模和实验，分子相互作用对RMT的整个过程，基于 我们将优化NC通过BBB的运输。模拟和体外细胞培养实验 将带来关键的，新的见解和更深入地了解RMT的机制。的关键创新 我们提出的模型是将原子模拟与介观模型相结合， 对RMT的系统研究。膜模型与随机结合的结合 该模型也是创新的，能够对具有极端变形的RMT进行连贯的探索。此外，本发明还提供了一种方法， 原子模拟中的粗粒度力场是新颖的，对于捕获构象是至关重要的。 蛋白质相互作用的信息。如果成功，这将是第一个研究转胞吞作用的模型。 NCs通过内皮细胞的转运机制，这可以扩展到研究其他器官的转运机制。

Transport of biologics, including antibodies, enzymes, drug molecules, etc., to the brain parenchyma is challenging due to the blood-brain barrier (BBB). A key strategy to efficiently deliver drugs across BBB is to encapsulate drugs inside a nanocarrier/nanocell (NC), then functionalize NC with bioactive peptides, proteins, or antibodies with their receptors highly expressed at targeted sites, leading to receptor-mediated active transport. The effective delivery of NCs through receptor-mediated transcytosis (RMT) is a highly complex and multiscale process, which is difficult to investigate through scale-specific techniques (both experimentally and numerically). In this project, we propose to establish an interdisciplinary research program to investigate RMT of NCs through comb"inat1on of multiscale modeling and "in vitro cell culture experiments. The proposed research aims are: (a) to develop a multiscale model for RMT through BBB, which includes a mesoscale stochastic model for NC binding, internalization and expulsion as well as an atomistic model for specific protein-protein and protein-lipid interactions at molecular level; (b) to validate our multiscale model through comparison with the in vitro cell culture experiments on the effect of ligand density; and (c) to explore the effects of particle size, particle shape/type, ligand density, ligand type, as well as the molecular interactions on the overall process of RMT through both modeling and experiments, based on which we will optimize the NC transport through BBB. The simulations and in vitro cell culture experiments will bring critical, new insight and a deeper understanding of the mechanism of RMT. The key innovation of our proposed models lay in the integration of atomistic simulations with mesoscopic model, which allows for systematic investigation of the RMT. The combination of the membrane model with the stochastic binding model is also innovative and enables a coherent exploration of RMT with extreme deformations. In addition, the coarse-grained force field in atomistic simulations is novel and crucial to capture the conformational information for protein-protein interactions. If successful, this will be the first model to study transcytosis of NCs through endothelial cells, which could be extended to study the transport mechanisms in other organs.