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Role of CD13 in Ischemic Stroke

CD13 在缺血性中风中的作用

基本信息

批准号：
9979469
负责人：
Anjali Chauhan
金额：
$ 44.41万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2022-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9979469
关键词：
Acute Address Affect Age Alteplase Animal Model Animal Testing Animals Antigen Presentation Atrophic Behavioral Blood Vessels Brain Cause of Death Cell Adhesion Cells Cerebrovascular Circulation Chronic Chronic Phase Clinical Research Clinical Trials Data Effectiveness Elderly Endothelial Cells Endothelium Exclusion Criteria Failure Female Functional disorder Histologic Hour Immune Immune response Infarction Infiltration Inflammation Inflammatory Injury Ischemia Ischemic Stroke Knockout Mice Lead Leukocytes Measures Membrane Metalloproteases Middle Cerebral Artery Occlusion Mus Myelogenous Myeloid Cells Nature Neurologic Neurologic Deficit Outcome Pathway interactions Peptides Peripheral Pharmaceutical Preparations Pharmacology Pharmacotherapy Phase Play Process Recovery Research Design Risk Role Site Stimulus Stroke Systemic disease Tamoxifen Testing Therapeutic Time Tissues Tumor-infiltrating immune cells Ubenimex Up-Regulation Work acute stroke aged alanine aminopeptidase angiogenesis blood-brain barrier disruption cell motility cell type chronic stroke clinically relevant cytokine disability drug development expectation experimental study functional outcomes healing improved improved outcome inhibitor/antagonist injury recovery juvenile animal knockout animal male monocyte neurogenesis neuroinflammation neuroprotection neutrophil novel novel therapeutics post stroke preclinical study repaired stroke model stroke recovery stroke therapy tissue injury

项目摘要

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).

项目描述中风是全球长期残疾的主要原因。多个机制参与了缺血性卒中的病理生理学，包括血脑屏障破坏、小胶质细胞活化和浸润的免疫细胞。在临床前研究中显示出神经保护作用的药物过多，在临床试验中的疗效。多种因素导致了这些令人失望的失败，包括研究设计，使用不适当的动物模型（即专门使用年幼动物），不切实际的治疗窗口（急性与慢性）和不良的目标选择。中风导致双相损伤：急性（数分钟至数小时）和慢性（数周月）的伤害。在急性损伤阶段，内源性和浸润性外周免疫之间的相互作用细胞导致神经炎症。然而，在慢性期，中风早期抑制循环白细胞，尤其是单核细胞和中性粒细胞的迁移点会减少神经炎症。此外，振兴恢复过程，包括血管生成，有利于卒中后的长期功能结局。CD 13是一种膜结合的金属蛋白酶，上调单核细胞和嗜中性粒细胞并促进它们的迁移。另一方面，CD 13上调在损伤后的修复中发挥作用。拟议的工作将检查CD 13在中风后炎症和恢复。将在CD 13敲除动物中进行机制研究; CD 13 在骨髓细胞和内皮细胞中的缺失将使我们能够研究其在急性损伤和术后恢复中的作用。（目标1）。然后，我们将确定CD 13抑制的药理学功效（急性Vs. 慢性期），在临床相关的老年中风模型中使用特异性抑制剂乌苯美司（目的2）。