Rational Design of Surface Modified Nanoparticles for Modulation of Amyloid Protein Aggregation

非技术性描述淀粉样蛋白的聚集涉及广泛的过程，包括许多疾病的发病机制（阿尔茨海默病，2型糖尿病等）。以及在与诸如食品生产或水净化的应用相关的生物污垢中。因此，开发防止或减缓这种聚集的工具在治疗和工业过程中都很重要。 这项工作的主要目标是开发一个平台，用于合理设计能够调节淀粉样蛋白聚集的纳米颗粒。 通过耦合实验和分子建模，该项目将开发一种新的描述在生物环境和合成材料的界面处发生的复杂相互作用。 该理论可以应用于预测纳米颗粒-蛋白质相互作用对淀粉样蛋白聚集的影响，从而代表了一个设计平台。 通过推进我们对纳米颗粒和淀粉样蛋白之间相互作用的理解，我们将能够合理设计用于治疗衰弱性疾病的纳米颗粒，减少不必要的生物污染，并促进工业应用。 参与该项目的研究生和本科生将获得尖端的实验技术和前沿建模方法，以培养他们未来在这些领域的职业生涯。技术说明拟议的研究考虑表面改性纳米粒子的淀粉样蛋白聚集的调制，这在疾病和工业过程中起着有害的作用。最近，纳米颗粒已经成为选择性蛋白质相互作用的有吸引力的工具。纳米颗粒的表面性质、大小和形状可以精确控制，因此纳米颗粒提供了一个理想的可调平台来调节淀粉样蛋白聚集。这项工作的主要目标是耦合实验和分子建模，以开发一种新的描述发生在生物环境和合成材料的界面处的相互作用的复杂耦合。 这些相互作用可随后用于调节淀粉样蛋白聚集的纳米颗粒的合理设计。这项研究是由中心假设，即纳米颗粒诱导的局部溶液环境的变化驱动他们的能力，影响淀粉样蛋白聚集。 实验和建模的耦合将提供创建设计平台所需的基本理解，用于构建影响蛋白质聚集的纳米结构生物材料界面。 首先，完全原子分子模拟将结合详细的分子理论来描述当地的解决方案的环境。 其次，将实施淀粉样蛋白聚集的分子热力学模型。 最后，纳米粒子和淀粉样蛋白的分子水平理论将被耦合到量化如何一个单一的纳米粒子影响当地的解决方案的条件，影响聚集体的稳定性。 该耦合模型将用于合理设计和合成表面修饰的纳米颗粒，以实验评估其对淀粉样蛋白聚集的预测影响。 实验数据和理论预测之间的协议将证实所提出的hypothes.The协作性质的研究环境中创建的这个项目将被利用，以促进生物医学工程教育的研究和课堂设置。 拟议的研究将建立一个夏季本科生研究实习，学生将完成补充计算和实验研究任务。为了向大学预科学生介绍这一研究领域，将开发一个基于设计的模块，使学生熟悉蛋白质聚集应用的生物材料设计概念。总之，这些努力将为本科生和大学预科生提供工程技术如何促进生物现象控制的理解。

Non-Technical DescriptionThe aggregation of amyloid proteins is involved in a wide range of processes including the pathogenesis of numerous diseases (Alzheimer's disease, type 2 diabetes, etc.) as well as in biofouling associated with applications such as food production or water purification. The development of tools to prevent or slow this aggregation would thus be important in both therapeutics and industrial processes. The main goal of this work is to develop a platform for the rational design of nanoparticles capable of modulating amyloid protein aggregation. By coupling experiments and molecular modeling, this project will develop a novel description of the complex interactions that occur at the interface of biological environments and synthetic materials. This theory can then be applied to predict the influence of nanoparticle-protein interactions upon amyloid protein aggregation, thus representing a design platform. By advancing our understanding of interactions between nanoparticles and amyloid proteins, we will be able to rationally design nanoparticles for treating debilitating diseases, reduce unwanted biofouling, and facilitate industrial applications. Graduate and undergraduate students participating in the project will acquire cutting-edge experimental techniques and frontier modeling approaches to train them for future careers in these areas.Technical DescriptionThe proposed research considers surface modified nanoparticles for the modulation of amyloid protein aggregation, which plays a deleterious role in disease and industrial processes. Recently, nanoparticles have emerged as attractive tools for selective protein interactions. Nanoparticle surface properties, size, and shape can be accurately controlled, and therefore nanoparticles provide an ideal tunable platform to modulate amyloid protein aggregation. The main goal of this work is to couple experiments and molecular modeling to develop a novel description of the complex coupling of interactions that occur at the interface of biological environments and synthetic materials. These interactions can be subsequently used for the rational design of nanoparticles for modulation of amyloid protein aggregation. The research is guided by the central hypothesis that nanoparticle-induced changes in the local solution environment drive their ability to influence amyloid protein aggregation. The coupling of experiments and modeling will provide the fundamental understanding needed to create design platforms for building nanostructured biomaterial interfaces that influence protein aggregation. First, fully atomistic molecular simulations will be used in conjunction with detailed molecular theory to describe the local solution environment. Second, a molecular thermodynamic model of amyloid protein aggregation will be implemented. Finally, molecular level theories for nanoparticles and amyloid proteins will be coupled to quantify how a single nanoparticle influences local solution conditions to affect the stability of aggregates. This coupled model will be used to rationally design and synthesize surface modified nanoparticles to experimentally evaluate their predicted effects on amyloid protein aggregation. Agreement between experimental data and theoretical predictions will substantiate the proposed hypothesis.The collaborative nature of the research environment created in this project will be exploited to promote biomedical engineering education within both research and classroom settings. The proposed research will establish a summer undergraduate research internship in which students will complete complementary computational and experimental research tasks. To introduce this research area to pre-college students, a design-based module will be developed that familiarizes students with the concepts of biomaterial design for applications in protein aggregation. Together, these efforts will provide both undergraduate and pre-college students with an understanding of how engineering technologies can facilitate the control of biological phenomena.