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Self-Immolative Bolaamphiphiles for Signal Transduction Across Bilayer Membranes

用于跨双层膜信号转导的自焚 Bola 两亲物

基本信息

批准号：
2103598
负责人：
Bradley Smith
金额：
$ 49.13万
依托单位：
University of Notre Dame
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=2103598&HistoricalAwards=false
关键词：
Self Immolative Bolaamphiphiles Signal Transduction

项目摘要

With the support of the Macromolecular, Supramolecular and Nanochemistry Program in the Division of Chemistry, Professor Bradley Smith of the University of Notre Dame will develop a series of molecules that can transmit chemical signals across thin membranes similar to those that surround and protect all living cells. Much of the research work will use simple membrane bubbles called liposomes, and a set of experiments will elucidate the chemical and physical factors controlling the speed and intensity of the transmembrane signaling. The signaling molecules are designed to span the membrane and transduce an enzyme-catalyzed chemical reaction input on one side of the membrane into an observable optical signal on the other. These studies are expected to deepen fundamental understanding of how signals are transduced across membranes and will help pave the way toward successful development of synthetic living cells. As part of a complementary educational project, Professor Smith and his students will modernize the free internet workbook Organic Structure Elucidation which is used by hundreds of high school and college-level STEM instructors for remote learning. All planned activities will be conducted by a diverse group of talented graduate and undergraduate students, who will receive integrated training in experimental chemical research, data analysis, and scientific communication.The membrane-spanning synthetic signaling molecules being targeted here, self-immolative bolaamphiphiles, have chemical structures comprised of a hydrophilic trigger group connected by a self-immolative oligomeric linker to a releasable fluorophore. Enzymatic cleavage of the trigger group (input signal) will occur outside a bilayer membrane and the signal will subsequently be transduced by spontaneous depolymerization (self-immolation) of the linker into an observable fluorescence response (output signal) on the other side of the membrane. The results of bulk-phase fluorescence experiments are expected to provide atomic-level insight concerning the crucial molecular and physical factors that control the kinetics of transmembrane signal transduction. Studies using phase-separated membranes will test central concepts concerning membrane domain clustering as a process to modulate enzyme-triggered transmembrane signaling. Imaging experiments that compare the same signal transduction process occurring simultaneously in a cohort of separate giant liposomes will enable quantification of system heterogeneity. A practical outcome will be a new class of sensing liposomes with fluorescent output that can simultaneously image spatiotemporal changes of several different enzymes within living cells.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

在化学系大分子、超分子和纳米化学项目的支持下，圣母大学的布拉德利·史密斯教授将开发一系列分子，这些分子可以通过类似于包围和保护所有活细胞的薄膜传递化学信号。许多研究工作将使用被称为脂质体的简单膜泡，一系列实验将阐明控制跨膜信号传导速度和强度的化学和物理因素。信号分子被设计成跨越膜，并将膜一侧的酶催化化学反应输入转化为另一侧可观察到的光信号。这些研究有望加深对信号如何跨膜转导的基本理解，并将有助于为成功开发合成活细胞铺平道路。作为补充教育项目的一部分，史密斯教授和他的学生将对免费的互联网练习册《有机结构阐释》进行现代化改造，这本书被数百名高中和大学级别的STEM教师用于远程学习。所有计划的活动将由一群有才华的研究生和本科生进行，他们将在实验化学研究、数据分析和科学交流方面接受综合训练。本文所针对的跨膜合成信号分子是自焚型亲水两亲分子，其化学结构由亲水性触发基团组成，由自焚型低聚连接物连接到可释放的荧光团。触发基团的酶切（输入信号）将在双层膜外发生，随后该信号将通过连接体的自发解聚（自我牺牲）转导为膜另一侧可观察到的荧光响应（输出信号）。体相荧光实验的结果有望提供有关控制跨膜信号转导动力学的关键分子和物理因素的原子水平的见解。使用相分离膜的研究将测试有关膜结构域聚类作为调节酶触发的跨膜信号传导过程的中心概念。成像实验比较在一组分离的巨脂质体中同时发生的相同信号转导过程，将使系统异质性的量化成为可能。一个实际的结果将是一类具有荧光输出的新型传感脂质体，可以同时成像活细胞内几种不同酶的时空变化。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。