Mechanisms of Co-Polymer-Mediated Neuroprotection

尽管对导致急性损伤后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，目前尚无治疗方法。我 已经发现F-68，一种由聚乙烯和聚丙烯组成的三嵌段共聚物，可以深刻地拯救神经元 从严重损伤的体外和体内，通过修复丢失的神经细胞质膜的完整性。瞄准 含有这种聚合物的质膜构成了一种新的、有效的和潜在的重要的治疗方法 抢救急性损伤后的神经元。本应用程序的主要目标是了解Tri-Block如何 共聚物与受损的膜相互作用，拯救受损的神经元。为了达到这一目标，我们将 研究这些共聚物与日益复杂的膜系统的相互作用：巨型单层膜 囊泡(GUV)、封闭的红细胞幽灵和培养的海马神经元。这样做的具体目的是 建议是：1)确定共聚结构在膜修复和膜修复效果中所起的作用 共聚体系结构在神经保护中的重要性。2)明确脂类包装的作用 诱导F-68插入和修复质膜的浓度。3)确定合作伙伴的作用 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。4) 确定膜脂质过氧化和膜流动性变化在诱导F-68细胞中的作用 质膜的插入和修复。

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.