Molecular-Scale Membrane Curvature Generation in Protein-Lipid Systems: Electrostatics, Hydrophobicity, and Geometry

该奖项由加州大学洛杉矶分校材料研究部生物材料项目颁发，旨在利用最近在细胞膜自组装背景下发展起来的静电和疏水性知识。如何以及为什么蛋白质-脂质相互作用产生分子尺度的膜曲率将根据目前对抗菌剂和凋亡蛋白的兴趣进行研究。合理设计抗菌剂和调控细胞凋亡或程序性细胞死亡将是这些研究的潜在结果。在抗微生物药物方面，迫切需要有效的药物来杀死新的耐药细菌菌株。抗菌肽（AMPs）具有杀灭细菌的作用，存在于多种动物体内，但其作用机制尚不清楚。该项目将研究一类对人类特别重要的新型抗菌肽，称为防御素，以了解防御素如何以及为什么通过在细胞膜上产生孔而不是在哺乳动物细胞膜上杀死细菌。该项目的第二部分是研究B细胞淋巴瘤2 （BCL2）蛋白，该蛋白负责程序性细胞死亡，这是一种通过诱导线粒体孔隙形成来杀死不需要或有缺陷的细胞的过程。该项目计划量化BCL2如何诱导导致细胞死亡的线粒体膜的拓扑变化。就更广泛的影响而言，这个多学科项目预计将为研究生和本科生提供充足的教育机会。此外，所提出的研究课题有利于学术和产业就业的培训。该项目将为代表性不足的本科生和退伍军人提供研究实习机会。有一个具体的计划，将该研究项目的结果纳入研究者的高级本科/研究生课程。将向当地高中的经济困难学生提供补充强化教育模块。该研究项目旨在利用最近发展的物理学知识来理解两个相关问题，一个影响传染病，另一个影响癌症。该项目的第一部分将是开发新的抗菌剂。随着耐药菌感染发生率的增加，迫切需要新的抗生素。抗菌肽（AMPs）已经杀死了数百万年的细菌，存在于广泛的动物中，但其作用机制尚不清楚。该项目的一个目标将是研究一类对人类特别重要的抗菌肽，称为防御素。该项目将研究这些肽通过在细菌细胞膜上制造孔而不是在人类细胞膜上杀死细菌的机制。这些研究建立的知识库将有利于开发新的合成抗菌素。该项目的第二部分将是研究导致程序性细胞死亡的蛋白质。这些蛋白质，B细胞淋巴瘤2 (BCL2)，负责所谓的程序性细胞死亡，通过这一过程，不需要的或有缺陷的细胞被杀死。由于一些尚不清楚的原因，癌细胞不会这样做。通过这个研究项目，研究人员将定量地研究这些蛋白质是如何完成这种程序性细胞死亡的。这些研究的成功结果可能会导致新的治疗策略的发展，用于治疗各种癌症。就更广泛的影响而言，这项计划的多学科性质将为学生提供充足的教育机会，为他们提供学术和工业就业培训。提案中详细介绍了为代表性不足的本科生和老学生提供研究实习的具体计划。此外，这项研究的结果将被纳入PI的高级本科/研究生课程。还将向当地高中的经济困难学生提供补充教育模块。

This award by the Biomaterials program in the Division of Materials Research to University of California Los Angeles aims to leverage recently developed knowledge of electrostatics and hydrophobicity in the context of self assembly in cell membranes. How and why protein-lipid interactions generate molecular scale membrane curvature will be studied with respect to current interest in antimicrobials and apoptosis proteins. The rational design of antimicrobials and the regulation of apoptosis, or programmed cell death would be the potential outcomes of these studies. With respect to antimicrobials, there is an urgent need for effective ones to kill new strains of antibiotic-resistant bacteria. Antimicrobial peptides (AMPs) that kill bacteria occur in a broad range of animals, but their mechanisms of action are not well understood. A new class of AMPs of particular importance to humans called defensins will be studied with this project in developing an understanding how and why defensins kill bacteria by producing pores in their cell membranes but not in mammalian cell membranes. The second part of the project is to study B cell lymphoma 2 (BCL2) proteins, which are responsible for programmed cell death, a process through which unwanted or defective cells are killed by inducing pore formation in mitochondria. This project plans to quantify how BCL2 induces topological changes in the mitochondrial membrane that cause the death of cells. With respect to broader impact, this multi-disciplinary project is expected to provide ample educational opportunities to both graduate and undergraduate students. In addition, the proposed research topics are conducive to training for academic and industrial employment. The project will provide research internships to underrepresented undergraduate students and veterans. There are specific plans for the incorporation of results from this research project into the advanced undergraduate/graduate classes of the investigator. Supplemental enrichment educational modules will be provided to economically disadvantaged students at the local high schools.This research project aims to leverage recently developed knowledge in physics to understand two related problems, one that impacts infectious diseases, and second one that impacts cancer. The first part of this project would be development of new antimicrobials. There is an urgent need for new antibiotics with the increasing incidences of infections by antibiotic-resistant bacteria. Antimicrobial peptides (AMPs) that have killed bacteria for millions of years occur in a broad range of animals, but their mechanism of actions are not well understood. One objective of this project will be studying a class of antimicrobial peptides of particular importance to humans called defensins. Mechanisms by which these peptides kill bacteria by creating pores in their cell membranes, but not in human cell membranes, will be investigated by this project. The knowledge base developed by these studies would be of benefit in developing new synthetic antimicrobials. The second part of this project will be in studying proteins that are responsible for program cell death. These proteins, B cell lymphoma 2 (BCL2), are responsible for so-called programmed cell death, a process through which unwanted or defective cells are killed. For reasons not well understood, cancer cells do not do this. With this research project, the investigators will examine quantitatively how this programmed cell death is accomplished by these proteins. A successful outcome from these studies could lead to the development of new therapeutic strategies in the treatment of a wide range of cancers. With respect to broader impacts, this multi-disciplinary nature of this project will provide ample educational opportunities to students in providing them training for academic and industrial employment. Specific plans are detailed in the proposal to provide research internships to underrepresented undergraduate and veteran students. In addition, results from this research will be incorporated into the PI's advanced undergraduate/graduate classes. Supplemental educational modules also will be provided to economically disadvantaged students at local high schools.