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Mechanisms of Co-Polymer-Mediated Neuroprotection

共聚物介导的神经保护机制

基本信息

批准号：
7583289
负责人：
JEREMY D MARKS
金额：
$ 4万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-15 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7583289
关键词：
4 hydroxynonenal Acute Architecture BODIPY Biological Assay Brain Injuries Cell Membrane Permeability Cell membrane Cells Cessation of life Cholesterol Complex Disruption Electroporation Erythrocyte Ghost Erythrocytes Extravasation Fenton&apos s reagent Fluorescence Glucose Hippocampus (Brain)Hypotonic Solutions Image In Vitro Injury Label Lecithin Length Life Lipid Bilayers Lipid Peroxidation Lipids Malondialdehyde Measures Mediating Membrane Membrane Fluidity Membrane Lipids Neurobiology Neurologic Neurons Oxidative Stress Oxides Oxygen Patients Permeability Phospholipids Physical Chemistry Polyethylene Polyethylenes Polymers Polypropylenes Rate Rattus Research Personnel Role Role playing therapy Series Source Staining method Stains Stimulus Stress Superoxides Supplementation System Testing Time Tube Vesicle Vitamin K 3 Width density deprivation disability extracellular fluorexon in vivo injured mortality multidisciplinary neuron loss neuronal survival neuroprotection novel oxidation peroxidation repaired seal time use

项目摘要

Despite detailed understanding of the cellular mechanisms leading to neuronal death following acute injury, acute brain injury is an important cause of neurologic disability in patients for which there is no treatment. I have found that F-68, a tri-block co-polymer of polyethylene and polypropylene, profoundly rescues neurons from severe injury in vitro and in vivo, by repairing the loss of neuronal plasma membrane integrity. Targeting the plasma membrane with this polymer constitutes a novel, effective, and potentially important treatment for rescuing neurons following acute injury. The major objective of this application is to understand how tri-block co-polymers interact with damaged membranes to rescue injured neurons. To achieve this objective, we will study the interactions of these co-polymers with increasingly complex membrane systems: giant unilamellar vesicles (GUVs), sealed erythrocyte ghosts and cultured hippocampal neurons. The Specific Aims of this proposal are: 1) Identify the role played by co-polymer architecture in the efficacy of membrane repair and the importance of co-polymer architecture in neuroprotection. 2) Identify the role played by lipid packing density in inducing F-68 insertion into and repair of the plasma membrane. 3) Identify the role played by co- polymers in decreasing oxidative stress and peroxidative plasma membrane damage during acute injury. 4) Identify the role played by membrane lipid peroxidation and changes in membrane fluidity in inducing F-68 insertion into and repair of the plasma membrane.

尽管对急性损伤后导致神经元死亡的细胞机制有详细的了解，急性脑损伤是导致患者神经功能障碍的重要原因，对此没有治疗方法。我已经发现，F-68，一种聚乙烯和聚丙烯的三嵌段共聚物，通过修复神经元质膜完整性的丧失，在体外和体内从严重损伤中恢复。靶向具有这种聚合物的质膜构成了一种新的、有效的和潜在重要的治疗方法，拯救急性损伤后的神经元。本应用程序的主要目标是了解三块共聚物与受损的膜相互作用以拯救受损的神经元。为达致这个目标，我们会研究这些共聚物与日益复杂的膜系统的相互作用：囊泡（GUV），密封的红细胞血影和培养的海马神经元。具体目标是建议包括：1）确定共聚物结构在膜修复功效中所发挥的作用，共聚物结构在神经保护中的重要性。2)确定脂质包装所起的作用诱导F-68插入和修复质膜的密度。3)确定共同体发挥的作用，聚合物在降低急性损伤期间的氧化应激和过氧化质膜损伤中的作用。四、确定膜脂质过氧化和膜流动性的变化在诱导F-68中所起的作用插入和修复质膜。