Mechanisms of Co-Polymer-Mediated Neuroprotection

描述(申请人提供)：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，但急性脑损伤是导致患者神经功能障碍的重要原因，目前尚无治疗方法。我发现，F-68，一种由聚乙烯和聚丙烯组成的三嵌段共聚物，通过修复神经细胞质膜完整性的丧失，在体外和体内深刻地挽救了严重损伤的神经元。用这种聚合物靶向质膜构成了一种新的、有效的、潜在的重要治疗方法，用于抢救急性损伤后的神经元。这一应用的主要目的是了解三嵌段共聚物如何与受损的细胞膜相互作用，以拯救受损的神经元。为了实现这一目标，我们将研究这些共聚物与日益复杂的膜系统的相互作用：巨大的单层囊泡(GUV)、封闭的红细胞幽灵和培养的海马神经元。这项建议的具体目的是：1)确定共聚结构在膜修复效果中所起的作用以及共聚结构在神经保护中的重要性。2)确定脂质堆积密度在诱导F-68插入和修复质膜中所起的作用。3)明确共聚物在减轻急性损伤时氧化应激和过氧化质膜损伤中的作用。4)明确膜脂质过氧化和膜流动性改变在诱导F-68插入和修复质膜中的作用。

DESCRIPTION (provided by applicant): 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.