Remote ischemic Conditioning Promotes Cerebrovascular Recovery after Intracerebral Hemorrhage

远程缺血调理促进脑出血后脑血管恢复

• 批准号: 10459588
• 负责人: KRISHNAN M. DHANDAPANI
• 金额: $ 38.09万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10459588
• 关键词: 5' -AMP-activated protein kinase; Acute; Affect; Age; American; Anti-Inflammatory Agents; Architecture; Arteries; Blood Pressure; Blood Vessels; Blood capillaries; Bone Marrow; Brain; Brain Injuries; Brain hemorrhage; Canis familiaris; Cells; Cerebral Amyloid Angiopathy; Cerebral Ischemia; Cerebral hemisphere hemorrhage; Cerebral small vessel disease; Cerebrovascular Circulation; Chronic; Clinical; Clinical Trials; Cyclic AMP-Dependent Protein Kinases; Development; Drug Kinetics; Endothelium; Essential Fatty Acids; Excision; Exercise; Exhibits; Extracellular Matrix Proteins; FDA approved; Goals; Hematoma; Human; Hypertension; Immune; Inflammation; Intervention; Intracranial Arterial Stenosis; Ischemia; Ischemic Stroke; Limb structure; Mediating; Mediator of activation protein; Medical Assistance; Metabolic; Mus; Myelogenous; Myeloid Cell Activation; Myocardial Infarction; Nervous System Physiology; Neurologic; Neurological outcome; Neuroprotective Agents; Nutrient; Omega-3 Fatty Acids; Outcome; Pathway interactions; Patients; Phase I Clinical Trials; Pre-Clinical Model; Production; Protein Kinase; Proteins; Quality of life; Recovery; Regulation; Research; Resolution; Rupture; Safety; Stroke; Subarachnoid Hemorrhage; Survivors; Testing; Therapeutic; Tissues; Vascular Dementia; Vascular remodeling; angiogenesis; arm; arteriole; blood vessel development; cerebrovascular; chromosome 1 loss; clinical translation; comorbidity; cost effective; dietary; disability; endothelial stem cell; improved; injured; innovation; ischemic conditioning; limb ischemia; macrophage; mortality; neovascularization; neural network; neurogenesis; neurological recovery; neurorestoration; preservation; repaired; response; restoration; sex; stem cells; targeted treatment; tissue repair; translational study; white matter injury

PROJECT SUMMARY Intracerebral hemorrhage (ICH), the most common form of hemorrhagic stroke, accounts for up to 15% of all strokes. ICH, which affects 67,000 Americans annually, induces the highest acute mortality and the worst long- term neurological outcomes of all types of stroke. Primary ICH is caused by the rupture of small vessels damaged by chronic hypertension or cerebral amyloid angiopathy. The resultant hematoma disrupts neural networks and damages the vascular architecture, culminating in a loss of brain function and the need for lifelong medical assistance. Re-establishment of a functional cerebrovascular network of small arteries and arterioles is a prerequisite for the removal of damaged tissue and for restoration of cerebral blood flow to deliver nutrients, trophic factors, and stem cells within the injured brain. Thus, there is a dire need for neurorestorative therapies that provide cerebrovascular recovery after ICH. Remote ischemic conditioning (RIC), the repetitive delivery of sub-lethal ischemia to a remote limb, demonstrated safety, versatility, and efficacy in early stage clinical trials; however, the utility of RIC after ICH remains understudied. The objective of this proposal is to test the overarching hypothesis that RIC induces vascular remodeling and improves long-term neurological function via anti-inflammatory myeloid cell activation after ICH. Specific Aim 1 will test the hypothesis that myeloid AMPKα1 mediates RIC-induced vascular repair after ICH. Specific Aim 2 will test the hypothesis that RIC increases angiogenesis via Del-1 release after ICH. Specific Aim 3 will test the hypothesis that delayed implementation of RIC improves chronic ICH outcomes in a sex- and age-independent manner. Expected outcomes of the proposed research include the identification of RIC as a clinically-safe, non-invasive intervention to promote cerebrovascular recovery after ICH. As ICH patients exhibit high permanent disability rates that diminish quality of life, our proposed research will identify a simple therapy to harness an endogenous pathway of neurological repair, providing an innovative and cost-effective approach to rehabilitate chronic ICH patients. .

项目摘要 脑内出血（ICH）是最常见的出血性中风形式，最多占全部的15％ 中风。 ICH每年影响67,000名美国人，诱发最高的急性死亡率和最糟糕的长期 所有类型的中风的术语神经结局。主要ICH是由损坏的小血管破裂引起的 通过慢性高血压或脑淀粉样血管病。由此产生的血肿破坏了神经网络和 损害血管结构，最终导致脑功能丧失和终身医学的需求 协助。重新建立小动脉和小动脉的功能性脑血管网络是 去除受损组织和恢复脑血流以提供营养的先决条件， 营养因素和受伤大脑内的干细胞。那很迫切需要神经训练疗法 ICH后提供脑血管恢复。远程缺血条件（RIC），重复交付 在远程肢体上，亚特拉的缺血在早期临床试验中表现出安全性，多功能性和有效性； 但是，ICH之后的RIC的实用性仍然被理解。该提议的目的是测试 RIC诱导血管重塑并改善长期神经功能的总体假设 通过ICH后，通过抗炎的髓样细胞激活。特定目标1将检验髓样的假设 AMPKα1介导ICH后RIC诱导的血管修复。特定目标2将检验RIC的假设 ICH后通过DEL-1释放增加血管生成。特定目标3将检验延迟的假设 RIC的实施以性别和年龄的方式改善了慢性成果。预期的 拟议研究的结果包括将RIC鉴定为临床安全的无创 干预措施以促进ICH后脑血管恢复。随着ICH患者表现出高永久残疾 降低生活质量的比率，我们提出的研究将确定一种简单的疗法来利用内源性 神经修复的途径，提供了一种创新且具有成本效益的方法来恢复慢性ICH 患者。 。