Collateral flow and stroke outcome

侧支血流和卒中结果

• 批准号: 9553470
• 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/9553470
• 关键词: Acute; Adoptive Transfer; Affect; Anatomy; Antibodies; Biological; 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; Hemorrhage; 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; Pharmacology; 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; recruit; response; stroke outcome; stroke risk; stroke trials; targeted treatment; therapeutic development; therapy development; tomography; treatment group

 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）： 侧支循环状态是缺血性卒中患者卒中结局和溶栓治疗反应的独立预测因子。遗传因素有助于原生侧支的范围和发展，而代谢综合征患者与急性缺血性卒中时不良侧支状态相关。糖尿病增加中风的风险，并加剧缺血性脑损伤，虽然糖尿病对侧支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，一个强大的招聘软脑膜侧支血流检测后立即大脑中动脉（MCA）闭塞C57 BL/6小鼠，并继续增长超过一个星期的过程。然而，在MCAO后立即在II型糖尿病db/db小鼠中侧支募集受损是明显的。在当前的应用中，我们试图研究软脑膜侧支损伤的机制。Aim 1将首先确定MCA卒中后软脑膜侧支循环中ACA至MCA的逆行血流补偿动力学及其对小鼠品系卒中结局的贡献，这些小鼠品系可用作侧支循环遗传变异的替代物或用于代谢疾病的病理生理学建模。目的2将阐明急性高血糖是否有助于II型糖尿病小鼠软脑膜侧支循环的损害，以及短期胰岛素治疗是否恢复中风后的侧支循环状态。目的3将通过流式细胞术确定有利于胶原生成/动脉生成的巨噬细胞表型。我们还将确定CD 36（M2巨噬细胞的标志物）在调节侧支血流中的作用。补充方法将确定通过药理学试剂增强CD 36表达是否促进糖尿病小鼠中的侧支流动，或者通过将对照骨髓细胞过继转移到糖尿病小鼠中是否挽救后者中的侧支状态。这项概念验证研究将为开发治疗干预措施提供基础，以增加缺血性中风治疗的侧支血流。