Collateral flow and stroke outcome

侧支血流和卒中结果

• 批准号: 9142660
• 负责人: JIALING LIU
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9142660
• 关键词: Acute; Adoptive Transfer; Affect; Antibodies; Biological; Blood; Blood Vessels; Bone Marrow Cells; Brain; C57BL/6 Mouse; CD36 gene; Centers for Disease Control and Prevention (U.S.); Cerebral Ischemia; Cerebrum; Chronic; Clinical; Collateral Circulation; Data; Defect; Development; Diabetes Mellitus; Diabetic mouse; Diagnosis; Disabled Persons; Disease; Exposure to; Financial compensation; Flow Cytometry; Foundations; Functional disorder; Future; Gene Expression; Genetic; Glucose; Herbicides; Hour; Hyperglycemia; Hypertension; Hypoglycemia; Impairment; Inbred BALB C Mice; Infarction; Inflammation; Inflammatory; Injury; Insulin; Investigation; Ischemic Brain Injury; Ischemic Stroke; Leukocytes; Link; Metabolic Diseases; Metabolic syndrome; Middle Cerebral Artery Infarction; Middle Cerebral Artery Occlusion; Military Personnel; Modeling; Mouse Strains; Mus; Non-Insulin-Dependent Diabetes Mellitus; Optical Coherence Tomography; Optics; Outcome; Oxidative Stress; Pathology; Patients; Phenotype; Population; Regulation; Reporting; Risk; Risk Factors; Role; Services; Site; Stroke; Structure; System; TLR4 gene; Technology; Testing; Therapeutic Intervention; Thrombolytic Therapy; Up-Regulation; Veterans; agent orange; brain tissue; db/db mouse; diabetic; genetic variant; glycemic control; improved; inhibitor/antagonist; macrophage; middle cerebral artery; monocyte; public health relevance; response; targeted treatment; therapy development; tomography; treatment group; vascular inflammation

 DESCRIPTION (provided by applicant): Collateral status is an independent predictor of stroke outcome, as well as response to thrombolytic therapies in patients with ischemic stroke. Genetic factors contribute to the extent and development of native collaterals, whereas patients with metabolic syndromes are associated with poor collateral status during acute ischemic stroke. Diabetes increases the risk of stroke and exacerbates ischemic brain damage, although the impact of diabetes on collateral dynamics remains to be established. Our preliminary data suggest that using Doppler optical coherent tomography, a robust recruitment of leptomeningeal collateral flow was detected immediately after middle cerebral artery (MCA) occlusion in C57BL/6 mice and it continued to grow over the course of one week. However, an impairment of collateral recruitment was evident in the type-II-diabetic db/db mice immediately after MCAO. In the current application, we seek to investigate mechanisms underlying leptomeningeal collateral impairment. Aim1 will first determine the dynamics of retrograde flow compensation from ACA to MCA in the leptomeningeal collateral circulation after MCA stroke and their contribution to stroke outcome in mouse strains that can be used as surrogates for genetic variant of collateral circulation or for modeling pathophysiology in metabolic diseases. Aim 2 will decipher whether acute hyperglycemia contributes to the impairment of leptomeningeal collateral flow in the type II diabetic mice and whether short-term insulin therapy restores the collateral status after stroke. Aim 3 will determine the macrophage phenotype favorable for collaterogenesis/arteriogenesis via flow cytometry. We will also ascertain the role of CD36, a marker for M2 macrophage, in regulating collateral flow. Complementary approaches will determine whether by enhancing CD36 expression by pharmacological agent promote collateral flow in the diabetic mice or whether by adoptive transfer of control bone marrow cells into diabetic mice rescues the collateral status in the latter. This proof-of-concept study will provide a foundation for the development of therapeutic interventions to augment collateral flow for the treatment of ischemic stroke.

 描述(由申请人提供)： 侧支状态是中风预后的独立预测因子，也是缺血性中风患者对溶栓治疗的反应。遗传因素影响自然络脉的范围和发展，而代谢综合征患者在急性缺血性卒中时侧支状态较差。糖尿病增加了中风的风险，并加剧了缺血性脑损伤，尽管糖尿病对侧支循环动力学的影响仍有待确定。我们的初步数据表明，使用多普勒光学相干断层扫描，在C57BL/6小鼠大脑中动脉(MCA)闭塞后立即检测到强劲的软脑膜侧支循环，并在一周内继续增长。然而，在II型糖尿病db/db小鼠MCAO后立即出现明显的侧支募集障碍。在目前的应用中，我们试图研究软脑膜侧支损伤的机制。AIM1将首先确定MCA卒中后软脑膜侧支循环中从ACA到MCA的逆行血流代偿动力学及其对卒中结局的贡献，可作为侧支循环遗传变异的替代或代谢性疾病的病理生理学模型。目的2阐明急性高血糖是否导致II型糖尿病小鼠软脑膜侧支循环受损，以及短期胰岛素治疗是否能恢复卒中后的侧支循环状态。目的3通过流式细胞术确定有利于侧支/动脉生成的巨噬细胞表型。我们还将确定M2巨噬细胞的标志物CD36在调节侧支循环中的作用。互补的方法将确定是通过药物增强CD36的表达来促进糖尿病小鼠的侧支循环，还是通过过继地将对照骨髓细胞转移到糖尿病小鼠来拯救后者的侧支循环状态。这项概念验证研究将为开发治疗干预措施以增加缺血性卒中的侧支循环提供基础。