CAREER: Scope and Limitations of Selective Membrane Fusion

膜融合是细胞生物学中一种基本的化学运输过程。虽然人们对控制融合的天然蛋白质机制的了解投入了很大的精力，但在开发理解膜融合的合成方法方面做的努力还很少。一般认为，天然融合的特异性来自于表面识别与局部膜破坏或应变的耦合。然而，大多数融合研究都是在使用类似识别基序的特定天然融合系统上进行的。该项目将膜融合作为一种非共价化学反应，而不是生物事件。该项目将通过开发合成的(非本地的)小分子融合系统来促进对物理融合过程的了解，这些系统允许对膜融合参数进行受控研究，并建立识别触发的膜融合的普遍性。该项目的重点是合成和最小的膜融合系统，该系统通过化学修饰和检查进行机械解剖。这个模型系统提供了一个密切研究融合的机会，这是更复杂的生物系统所不能提供的，因为在更复杂的生物系统中，涉及到多个调节因素，使分析变得模糊和复杂。膜融合是自然用于选择性、受控化学输送的一种方法。合成膜融合系统的发展直接有助于理解生物膜融合，此外还可能导致靶向药物输送和纳米隔间化学的战略。因此，这项研究将影响多个研究领域。更广泛的影响这个交叉学科项目通过发展非共价化学的新本科生和研究生班级来促进非共价化学思维的扩展。最重要的是开发了NSF-REEL(增强学习的研究经验)模块，本科生将参与基于HIV融合多肽序列的多肽库的合成和功能评估。其目的是探索HIV融合肽的灵活性的功能作用，而REEL模块是让本科生参与新研究的理想选择，同时提供关于肽、膜和非共价化学的指导。这个教学模块将把二年级有机化学的主题与艾滋病毒膜融合机制的研究结合起来，强调基础化学的重要性。基础化学还将通过校园外展活动进行营销，这将通过与校园学生领导层建立伙伴关系来实现。利用少数族裔学生组织安排的现有教育活动计划，将在校园宿舍举行每季度一次的非正式和一般性研讨会，向学生介绍俄亥俄州立大学的科学可能性，包括这个项目。该项目将基础研究与教育吸引力和趣味性结合起来。膜融合研究在靶向化疗和艾滋病毒研究中的生物医学应用很容易想象，应该会激励学生参与其中。该项目还包括一个针对少数族裔高中生的外展项目，在现有的一个项目中，利用少数族裔学生的参与者作为大使，大学生可以参观高中，进行科学演示。

Intellectual MeritMembrane fusion is a fundamental chemical transport process in cell biology. While much attention has been devoted to understanding the native protein machinery governing fusion, fewer efforts have been made in development of synthetic approaches towards understanding membrane fusion. It is thought that, generally, the specificity of native fusion derives from the coupling of surface recognition with local membrane disruption or strain. However, most fusion studies have been carried out on specific native fusogenic systems that employ similar recognition motifs. This project focuses on membrane fusion as a noncovalent chemical reaction rather than a biological event. The project will promote understanding of the physical fusion process through the development of synthetic (non-native), small molecule fusogenic systems that allow controlled studies of membrane fusion parameters and establish the generality of recognition triggered membrane fusion. The project focuses on a synthetic and minimal membrane fusion system that is subject to mechanistic dissection through chemical modification and examination. This model system provides an opportunity to closely study fusion not afforded by more complex biological systems in which there are multiple regulatory factors involved that obscure and complicate analysis. Membrane fusion is one method Nature uses for selective, controlled chemical delivery. Development of a synthetic membrane fusion system contributes directly to understanding of biomembrane fusion and additionally may lead to a strategy for targeted drug delivery and nanoscale compartmentalized chemistry. This research will therefore impact multiple fields of study. Broader ImpactThis cross-displinary project promotes expansion of non-covalent chemical thinking through the development of new undergraduate and graduate classes in noncovalent chemistry. Most significantly is the development of an NSF-REEL (Research Experiences to Enhance Learning) module where undergraduate students will participate in the synthesis and functional evaluation of a peptide library based on the HIV-fusion peptide sequence. The goal is to probe the functional role of flexibility of the HIV-fusion peptide, and the REEL module is ideal for involving undergraduates in novel research while simultaneously providing instruction on peptide, membrane and noncovalent chemistry. This educational module will integrate topics from sophomore organic chemistry with research on the HIV membrane fusion mechanism, underscoring the importance of basic chemistry. Basic chemistry will also be marketed through on-campus outreach activities, which will be achieved through partnership with on-campus student leadership. Using an existing program of educational events scheduled by minority student organizations, a quarterly series of informal and general seminars will be held at campus residence halls to introduce students to possibilities in science at Ohio State University, including this project. The project integrates basic research with educational appeal and interest. The easily imagined biomedical applications of membrane fusion research to targeted chemotherapy and HIV research should inspire students to participate. The project also includes an outreach program for minority high school students using minority student participants as ambassadors in an existing program where college students visit high schools to perform scientific demonstrations.