Mechanisms of Co-Polymer-Mediated Neuroprotection

描述（由申请人提供）：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，但急性脑损伤是患者神经功能障碍的重要原因，目前尚无治疗方法。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深刻地拯救神经元。用这种聚合物靶向质膜构成了一种新的，有效的，潜在的重要的治疗方法，用于抢救急性损伤后的神经元。本申请的主要目的是了解三嵌段共聚物如何与受损的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越来越复杂的膜系统的相互作用：巨大的单层囊泡（GUV），密封的红细胞血影和培养的海马神经元。该提案的具体目的是：1）确定共聚物结构在膜修复功效中所起的作用以及共聚物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)确定共聚物在急性损伤中减少氧化应激和过氧化质膜损伤中所起的作用。4)确定膜脂质过氧化和膜流动性变化在诱导F-68插入和修复质膜中所起的作用。

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.