CAREER: Scope and Limitations of Selective Membrane Fusion

膜融合是细胞生物学中一个基本的化学转运过程。 虽然很多注意力已经致力于了解天然蛋白质机制的融合，很少的努力已经在发展的合成方法，以了解膜融合。 一般认为，天然融合的特异性来源于表面识别与局部膜破坏或应变的偶联。 然而，大多数融合研究已经进行了特定的本地融合系统，采用类似的识别基序。 这个项目的重点是膜融合作为一个非共价化学反应，而不是一个生物事件。 该项目将通过开发合成（非天然）小分子融合系统促进对物理融合过程的理解，这些系统允许对膜融合参数进行受控研究，并建立识别触发膜融合的一般性。 该项目的重点是合成和最小的膜融合系统，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机会，密切研究融合不提供更复杂的生物系统，其中有多个监管因素，涉及模糊和复杂的分析。 膜融合是自然界用于选择性控制化学物质输送的一种方法。 合成膜融合系统的开发直接有助于理解生物膜融合，并且还可能导致靶向药物递送和纳米级区室化化学的策略。 因此，这项研究将影响多个研究领域。更广泛的影响这个跨学科的项目促进非共价化学思维的扩展，通过新的本科生和研究生班在非共价化学的发展。 最重要的是一个NSF-REEL（研究经验，以提高学习）模块的开发，本科生将参与基于HIV融合肽序列的肽库的合成和功能评估。我们的目标是探索HIV融合肽的灵活性的功能作用，REEL模块是让本科生参与新研究的理想选择，同时提供肽，膜和非共价化学的指导。 这个教育模块将整合从大二有机化学与艾滋病毒膜融合机制的研究课题，强调基础化学的重要性。 基础化学也将通过校园外展活动进行营销，这将通过与校园学生领导的伙伴关系来实现。利用少数民族学生组织安排的现有教育活动计划，将在校园霍尔斯举行一系列非正式和一般性的研讨会，向学生介绍俄亥俄州州立大学科学的可能性，包括这个项目。该项目将基础研究与教育吸引力和兴趣结合起来。膜融合研究在靶向化疗和HIV研究中的容易想象的生物医学应用应该激励学生参与。 该项目还包括一个针对少数民族高中生的外联方案，利用少数民族学生参与者作为现有方案的大使，大学生访问高中进行科学演示。

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.