Mechanisms Regulating Cerebral Arteriogenesis and Neurorestoration

 描述(由申请人提供)：促进血管重塑已成为神经恢复性治疗的一种潜在治疗方法。在脑损伤模型中，脑血管损伤导致脑血流不足，从而加剧神经细胞的丢失，导致运动和认知功能障碍。血管内皮细胞(ECs)对组织创伤有积极的反应。我们的新发现表明，称为EPH受体酪氨酸激酶(EphR)的细胞-细胞接触蛋白(EphR)及其肾上腺素配体(S)存在于脑小动脉内皮细胞上，并在限制小鼠脑损伤后的动脉形成中发挥核心作用。本应用的研究目标集中在EphR信号对小动脉重构和神经恢复的新的生长抑制机制(S)。内皮特异性的EphR缺失导致了显着的神经保护和血流量的恢复，这反映了动脉生成生长和促动脉生成因子产生的巨大变化。我们假设EphR信号的激活通过抑制微动脉血管重塑过程中的EC反应来介导神经组织损伤和功能障碍。为了测试这一点，我们将使用新的细胞特异性和可诱导的基因敲除小鼠，双报告标记和过继转移。我们还将使用增益功能输注和反向功能输注的方法来研究损伤诱导的动脉形成在神经恢复中的相关性和机制。这些研究将揭示一种新的治疗策略，以加强这一重要的适应过程，这将极大地影响急慢性头部损伤的治疗和管理。

 DESCRIPTION (provided by applicant): Promoting vascular remodeling has emerged as a potential therapeutic approach for neurorestorative therapy. Cerebral vascular trauma leads to inadequate cerebral blood flow which potentiates neuronal cell loss resulting in motor and cognitive deficits in models of brain injury. Endothelial cells (ECs) lining the blood vessels actively respond to tissue trauma. Our novel findings demonstrate, cell-to-cell contact proteins called Eph receptor tyrosine kinases (EphR), and their ephrin ligand(s), are present on cerebral arteriole ECs and play a central role in limiting arteriogenesis in the murine brain following injury. The research objectives in this application focus on the novel growth suppressive mechanism(s) of EphR signaling on arteriole remodeling and neural recovery. Endothelial-specific deletion of EphR resulted in significant neuroprotection and restoration of blood flow which reflects a monumental change in arteriogenic growth and production of pro-arteriogenic factors. We hypothesize that activation of EphR signaling mediates neural tissue damage and dysfunction by suppressing the EC response during arteriole vascular remodeling. To test this, we will employ novel cell-specific and inducible knockout mice, double reporter labeling and adoptive transfer. We will also investigate the relevance and mechanisms of injury-induced arteriogenesis in neural recovery using gain- and reverse-of-function infusion approaches. These studies will reveal a novel therapeutic strategy to enhance this important adaptive process which will greatly impact treatment and management of acute and chronic head injuries.