Role of CD13 in Ischemic Stroke

项目说明 中风是全球长期残疾的主要原因。这其中涉及多种机制。 缺血性卒中的病理生理学，包括血脑屏障的破坏、小胶质细胞的激活和渗透 外周免疫细胞。在临床前研究中，大量显示神经保护作用的药物未能证明 临床试验中的疗效。这些令人失望的失败有多种因素，包括研究设计、使用 不适当的动物模型(即只使用幼年动物)、不切实际的治疗窗口(急性VS 慢性)，目标选择不佳。中风导致双相损伤：急性(几分钟到几小时)和慢性(几周 到几个月)受伤。在急性损伤阶段，内源性免疫和浸润性外周免疫之间的串扰 细胞会导致神经炎症。然而，恢复过程是在慢性期被刺激的 卒中。早期抑制循环中的白细胞迁移，特别是单核细胞和中性粒细胞 积分将减少神经炎症。此外，激活包括血管生成在内的恢复性过程将 有利于卒中后的长期功能结果。CD13是一种膜结合的金属蛋白水解酶。 上调单核细胞和中性粒细胞，促进它们的迁移。另一方面，CD13上调 血管新生血管在损伤后的修复中起作用。这项拟议的工作将研究CD13在 卒中后炎症和康复。将在CD13基因敲除动物中进行机制研究； 髓系细胞和内皮细胞的缺失将使我们能够研究其在急性损伤和恢复中的作用 各冲程(目标1)。然后我们将确定CD13抑制(急性VS)的药理疗效。 慢性期)，在临床相关的老年卒中模型中使用特定的抑制剂乌苯美司(目标2)。

PROJECT DESCRIPTION Stroke is a leading cause of long-term disability worldwide. Multiple mechanisms are involved in the pathophysiology of ischemic stroke, including blood-brain barrier disruption, microglial activation, and infiltration of peripheral immune cells. A plethora of drugs showing neuroprotection in preclinical studies have failed to show efficacy in clinical trials. Multiple factors contribute to these disappointing failures, including study design, use of inappropriate animal models (i.e. exclusive use of young animals), impractical therapeutic windows (acute vs chronic), and poor target selection. Stroke results in biphasic injury: acute (minutes to hours) and chronic (weeks to months) injury. During the acute injury phase, the cross talk between intrinsic and infiltrating peripheral immune cells lead to neuroinflammation. However, restorative processes are stimulated during the chronic phase of stroke. Inhibition of circulating leukocyte transmigration, especially monocytes and neutrophils at early time points will reduce neuroinflammation. Additionally, invigorating restorative processes including angiogenesis will benefit long-term functional outcomes post stroke. CD13 is a membrane-bound metalloprotease, shown to upregulate monocytes and neutrophils and promote their transmigration. On the other hand, CD13 upregulation on angiogenic vessels plays a role in repair after injury. The proposed work will examine the effects of CD13 in post stroke inflammation and recovery. Mechanistic studies will be performed in CD13 knockout animals; CD13 deletion in myeloid cells and endothelial cells will allow us to study its role in acute injury and recovery post stroke respectively (Aim 1). We will then determine the pharmacological efficacy of CD13 inhibition (acute Vs chronic phase) using a specific inhibitor, Ubenimex, in a clinically relevant aged stroke model (Aim 2).