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 脑出血（ICH）是出血性卒中最常见的形式，占所有出血性卒中的15%。 中风ICH每年影响67，000名美国人，引起最高的急性死亡率和最严重的长期死亡率。 所有类型卒中的长期神经学结局。原发性脑出血是由受损的小血管破裂引起的 慢性高血压或脑淀粉样血管病。由此产生的血肿会破坏神经网络， 损害血管结构，最终导致脑功能丧失，需要终身医疗 援助.重建小动脉和小动脉的功能性脑血管网络是一种 这是去除受损组织和恢复脑血流以输送营养的先决条件， 营养因子和干细胞。因此，迫切需要神经恢复疗法 提供脑出血后脑血管恢复。远程缺血调节（RIC），重复提供 远端肢体亚致死性缺血，在早期临床试验中证明了安全性、多功能性和有效性; 然而，RIC在脑出血后的应用仍未得到充分研究。本提案的目的是测试 RIC诱导血管重塑并改善长期神经功能的总体假设 通过脑出血后的抗炎性骨髓细胞活化。特异性目的1将检验髓样细胞 AMPKα1介导ICH后RIC诱导的血管修复具体目标2将检验RIC 脑出血后通过Del-1释放增加血管生成。具体目标3将测试延迟的假设， RIC的实施以性别和年龄无关的方式改善了慢性ICH的结局。预计 拟议研究的结果包括将RIC确定为临床安全，非侵入性 干预促进脑出血后脑血管恢复。由于ICH患者表现出高度的永久性残疾， 降低生活质量的比率，我们提出的研究将确定一种简单的治疗方法来利用内源性 神经修复途径，为慢性ICH的康复提供了一种创新且具有成本效益的方法 患者 .