A supplement to: NIGMS 1R15GM144907-01A1 - Polymer-Lipid Particles investigated by Magnetic Resonance Spectroscopy

补充：NIGMS 1R15GM144907-01A1 - 通过磁共振波谱研究聚合物脂质颗粒

基本信息

批准号：
10801755
负责人：
Dominik Konkolewicz
金额：
$ 9.96万
依托单位：
MIAMI UNIVERSITY OXFORD
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-21 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10801755
关键词：
Administrative Supplement Binding Proteins Biophysics Calibration Cell physiology Cells Charge Clinical Trials Complement Detection Development Electron Spin Resonance Spectroscopy Environment Equipment Evaluation Funding Gel Chromatography Grant Health Hydrophobicity Infection Knowledge Length Lipid Bilayers Lipids Magnetic Resonance Spectroscopy Maintenance Measurement Membrane Membrane Lipids Membrane Proteins Mentors Methods Modernization Molecular Weight National Institute of General Medical Sciences Parents Polymer Chemistry Polymers Property Proteins Refractive Indices Research Secure Services Spin Labels Structure Structure-Activity Relationship System Techniques Technology Therapeutic Training U-Series Cooperative Agreements United States National Institutes of Health Virus Diseases Work amphiphilicity analytical tool cell growth regulation cost design detector graduate student insight instrument lens light scattering materials science mimetics nanometer nanoscale novel particle protein complex protein structure repaired response self assembly skills structural biology therapeutic development tool undergraduate student

项目摘要

A supplement to: NIGMS 1R15GM144907-01A1 - Polymer-Lipid Particles investigated by Magnetic Resonance Spectroscopy In response to: PA-20-272 - Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional) Funds are requested from NIGMS to obtain state of the art gel permeation chromatography (GPC) multi-angle light scattering (MALS) equipment to facilitate polymer analysis. Development of novel polymers is integral to NIGMS 1R15GM144907- 01A1, therefore having reliable methods for characterizing the polymers is essential to the project. Funds are being requested to obtain a TOSOH EcoSEC Elite including Refractive Index and LenS3 Multi-Angle Light Scattering Detector GPC MALS system capable of efficient and accurate polymer analysis to replace equipment that is from 2014. Project Summary/Abstract: Membrane proteins represent approximately 30% of all known proteins but only approximately 1% of solved protein structures. Despite recent advances in methods for membrane protein structural biology, knowledge about this important class of proteins lags behind their soluble counterparts. Membrane proteins are critical to numerous aspects of health, ranging from regulation cellular function and transport into and out of the cell, through to viral infections which use membrane proteins as part of the infection cycle. In almost 90% of newly developed and approved therapeutics, protein structural information was used to guide the development of the therapeutic molecules. Due to the limited and incomplete structural information on membrane proteins, the development of therapeutics and treatments that target membrane bound proteins is limited. A challenge in elucidating membrane protein structures is the lack of robust and appropriate lipid membrane mimetics. Existing membrane mimetics have limitations that can hinder membrane protein structural determination. This highlights an urgent need to develop lipid membrane mimetics which both provide a good approximation to the native lipid bilayer in terms of both structure and curvature, while also facilitating structural analysis of the membrane protein embedded in the mimetic. Yet polymer structure-function relationships are not well established for polymers that interact with lipids and membrane proteins. This project will use modern controlled polymer chemistry tools, to create a new class of polymers that will self-assemble with lipids. These self-assembled polymer-lipid systems will form well defined discs on the order of 10s of nanometers, giving lipid membrane mimetics suitable for the analysis of many membrane proteins. The advanced polymer chemistry techniques will enable fine tuning of polymer’s length, charges, and hydrophobicity. Polymer analysis through GPC MALS will give detailed information on the polymer’s properties, facilitation structure -function relationships between polymers and their self-assembled structures. Polymers will also be modified with spin-labels for electron paramagnetic resonance spectroscopy. Electron paramagnetic resonance spectroscopy methods will be used on polymers, lipids and membrane proteins modified with appropriate spin labels, providing insights into the local dynamics and proximities of the self-assembled polymer-lipid and polymer-lipid-membrane protein complexes. These insights can be used to guide the design of polymers for robust lipid membrane mimetics. Training and mentoring of undergraduate students as well as a graduate assistant will be a core feature of the proposed project. Undergraduate students will be integrated fully into the projects, including the polymer analysis, along with the graduate student, gaining skills in this field at the interface of materials science and biophysics.

补充：NIGMS 1R15GM144907-01A1 - 聚合物脂质颗粒通过磁共振波谱研究回应：PA-20-272 - 对现有 NIH 拨款的行政补充和合作协议（家长管理支持临床试验可选）向 NIGMS 申请资金以获得最先进的凝胶渗透色谱（GPC）多角度光散射（MALS）设备方便聚合物分析。新型聚合物的开发是 NIGMS 1R15GM144907- 的组成部分。 01A1，因此拥有可靠的方法来表征聚合物对于该项目正在申请资金以获得 TOSOH EcoSEC Elite，包括折射率和 LenS3 多角度光散射检测器 GPC MALS 系统能够进行高效、准确的聚合物分析，以取代 2014 年的设备。项目摘要/摘要：膜蛋白约占所有蛋白的 30% 已知的蛋白质，但仅解决了大约 1% 的蛋白质结构，尽管最近。膜蛋白结构生物学方法的进展，相关知识落后于可溶性分子的一类重要蛋白质是膜蛋白。对健康的许多方面都至关重要，包括调节细胞功能和转运进出细胞，直至使用膜蛋白的病毒感染作为感染周期的一部分，几乎 90% 是新开发和批准的。治疗学中，蛋白质结构信息被用来指导开发由于有关治疗分子的结构信息有限且不完整。膜蛋白，靶向疗法和治疗方法的开发膜结合蛋白的阐明是有限的。结构的原因是缺乏强大且合适的脂质膜模拟物。膜模拟物的局限性可能会阻碍膜蛋白的结构这凸显了开发脂质膜模拟物的迫切需要。两者在结构方面都提供了与天然脂质双层的良好近似和曲率，同时也有利于膜蛋白的结构分析然而，聚合物结构-功能的嵌入效果并不好。为与脂质和膜蛋白相互作用的聚合物而建立。该项目将使用现代受控高分子化学工具，创造一个新的类别将与脂质自组装的聚合物。系统将形成数十纳米数量级的明确定义的圆盘，从而提供脂质膜模拟物适用于分析许多膜蛋白。聚合物化学技术将能够微调聚合物的长度、电荷和通过 GPC MALS 进行聚合物分析将提供有关疏水性的详细信息。聚合物的性质、促进结构关系-聚合物和聚合物之间的功能它们的自组装结构也将通过自旋标签进行修饰。电子顺磁共振波谱。光谱方法将用于修饰聚合物、脂质和膜蛋白具有适当的自旋标签，提供对本地动态和邻近性的见解自组装的聚合物-脂质和聚合物-脂质-膜蛋白复合物。见解可用于指导坚固的脂质膜模拟物的聚合物设计。本科生和研究生助理的培训和指导将是拟议项目的核心特征，本科生将完全融入其中。与研究生一起参与包括聚合物分析在内的项目，获得材料科学和生物物理学交叉领域的技能。