Biopolymer Surfactants for Sealing Electroporated Membranes

用于密封电穿孔膜的生物聚合物表面活性剂

基本信息

批准号：
7320556
负责人：
RAPHAEL Carl LEE
金额：
$ 35.78万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-01 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7320556
关键词：
Acute Address Appendix Atomic Force Microscopy Binding Biocompatible Biopolymers Cell membrane Cells Cellular Membrane Cessation of life Cholesterol Condition Defect Development Disease Disruption Erythrocyte Ghost Exhibits Fibroblasts Fluorescence Microscopy Fluorescent Dyes Glycoproteins Goals Hour Imagery Injury Lead Length Lipid Bilayers Liquid substance Measurement Measures Mechanics Medicine Membrane Membrane Lipids Metabolic Methods Monitor Muscle Fibers Muscular Dystrophies Mutation Necrosis Octanes Paper Phenotype Plasma Membrane Lipid Bilayer Poloxamer 188 Poloxamine 1107 Production Property Range Reactive Oxygen Species Reperfusion Injury Research Personnel Resolution Resuscitation Series Standards of Weights and Measures Structure Surface Tension Techniques Testing Therapeutic Therapeutic Intervention Time Tissues Trauma Water Work cell type copolymer cytotoxic electrical property exhaustion fluorescence imaging free radical oxygen interfacial intermolecular interaction octane prevent programs repaired research study restoration seal size surfactant therapeutic effectiveness

项目摘要

DESCRIPTION (provided by applicant): Disruption of the plasma membrane's lipid bilayer structure with subsequent loss of its transport barrier function is the mechanism of tissue death in trauma, muscular dystrophies, reperfusion injuries and common diseases. Plasma membrane breakdown is followed by rapid metabolic energy exhaustion, then acute cellular necrosis. It is now well established that certain biocompatible multiblock copolymer surfactants, especially poloxamer 188, are effective in sealing of disrupted cell membranes and can prevent acute necrosis if delivered within a few hours after injury. (Appendix A). It is likely that P188 will soon be a standard component of trauma resuscitation fluids and will have a broad impact on medicine therapeutics. However, P188 may not be the ideal surfactant for membrane repair. It is rapidly degraded by oxygen free radicals into fragments that can be cytotoxic. Thus, it is necessary to determine the intermolecular interactions responsible for surfactant sealing of disrupted membranes so that more stable multiblock copolymer surfactants that seal membranes can be developed. We will test the prevailing hypothesis that sealing surfactants that seal bilayer lipid membranes do so by altering interfacial water structure, thus reducing membrane tension, which then permits reorganization of membrane lipids into a lipid bilayer. We will use established methods (Appendix C) to measure membrane tension while perturbing water structure around permeabilized membranes. The threshold membrane tensions for sealing will be determined for at least two different cell types. We plan to determine sealing efficacy as function of copolymer surfactant structure and determine suitable size of hydrophobic and hydrophilic moieties. We will also perform high resolution measurements of membranes structure and mechanical properties, before and after sealing (Appendix E). Finally, we will conduct studies in parallel to determine if surfactant rescued cells manifest normal phenotype during proliferation or exhibit effects of mutations caused by unrepaired DMA.

描述（由申请人提供）：质膜的脂质双层结构的破坏，随后丧失其运输屏障功能是创伤，肌肉营养不良，再灌注损伤和常见疾病的组织死亡机制。质膜分解之后是快速代谢能耗尽，然后是急性细胞坏死。现在可以很好地确定，某些生物相容性的多块共聚物表面活性剂，尤其是洛毒酵母188，可有效密封破坏的细胞膜，如果在受伤后的几个小时内递送，可以防止急性坏死。（附录A）。 P188可能很快将成为创伤复苏液的标准组成部分，并将对医学治疗剂产生广泛的影响。但是，P188可能不是膜修复的理想表面活性剂。它被氧自由基迅速降解为可以是细胞毒性的片段。因此，有必要确定负责破坏膜表面活性剂密封的分子间相互作用，以便可以开发密封膜的更稳定的多嵌段共聚物表面活性剂。我们将检验以下假设，即密封双层脂质膜的密封表面活性剂通过改变界面水结构来减少膜张力，从而降低膜张力，然后允许将膜脂质重组为脂质双层。我们将使用已建立的方法（附录C）来测量膜张力，同时扰动透化膜周围的水结构。至少两种不同的细胞类型将确定用于密封的阈值膜张力。我们计划确定密封功效是共聚物表面活性剂结构的功能，并确定合适的疏水和亲水部分的尺寸。我们还将在密封之前和之后对膜结构和机械性能进行高分辨率测量（附录E）。最后，我们将同时进行研究，以确定在增殖或表现出由未经修复的DMA引起的突变作用的表面活性剂是否表现出正常的表型。