Novel Targets and Therapeutic Interventions against Cerebral Ischemia-Reperfusion Injury

脑缺血再灌注损伤的新靶点和治疗干预措施

• 批准号: 10297340
• 负责人: Guohong Li
• 金额: $ 59.76万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10297340
• 关键词: 3' Untranslated Regions; Acute; Age; Animal Model; Atherosclerosis; Attenuated; Binding; Binding Sites; Blood; Blood Platelets; Brain; Brain Edema; Brain Infarction; Brain Injuries; CASP3 gene; Cerebral Ischemia; Complications of Diabetes Mellitus; Deterioration; Development; Dose; Female; Genes; Goals; Guidelines; Hemorrhage; Hippocampus (Brain); Hour; Hyperglycemia; Hyperlipidemia; Immunosuppression; Individual; Industry; Infection; Inflammatory Response; Injections; Injury; Intravenous; Ischemia; Ischemic Stroke; Life; Mediating; MicroRNAs; Modeling; Molecular; Molecular Mechanisms of Action; Molecular Target; Mus; Neurologic; Neurologic Deficit; Neuronal Injury; Neurons; Older Population; Oligonucleotides; Pathologic; Pathologic Processes; Patients; Plasminogen Activator Inhibitor 1; Recovery of Function; Regulation; Reperfusion Injury; Reperfusion Therapy; Role; Safety; Secondary to; Stroke; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Time; Treatment outcome; Update; acute stroke; age related; aged; animal mortality; base; cerebral microvasculature; combat; design; effective intervention; efficacy testing; endoplasmic reticulum stress; experimental study; gain of function; high risk; in vivo; innovation; loss of function; male; nervous system disorder; neuron apoptosis; neuron loss; novel; novel therapeutic intervention; post stroke; pre-clinical; prevent; response; stroke risk; stroke therapy; targeted treatment; therapeutic miRNA; thromboinflammation; thrombolysis; thrombotic; young adult

Project Summary/Abstract The cerebral ischemia/reperfusion (I/R) injury is a major challenge for the treatment of patients with acute ischemic stroke by intravenous (IV) thrombolysis and endovascular therapy. Currently, there is no effective intervention available to treat/prevent cerebral I/R injury. Emerging evidence suggests that thrombotic and inflammatory responses (thrombo-inflammation) and aberrant endoplasmic reticulum (ER) stress in the brain elicited by cerebral I/R contributes importantly to secondary brain injury and neurologic deterioration. In this proposal we wish to develop a novel miRNA-based therapeutic strategy to simultaneously target these pathological processes of cerebral I/R injury through distinct molecular mechanisms. Recently, decreased expression of miR-30c has been implicated in many pathological conditions in both patients and animal models. In preliminary studies, we show that miR-30c is highly expressed in blood platelets, cerebral microvessels, and cortical/hippocampal neurons in normal mice but its levels decline with age. miR-30c levels in both blood and brain are markedly decreased after ischemic stroke and elevating miR-30c by single IV injection of synthetic miR-30c mimic significantly protects against cerebral I/R injury. We further show that the increased expressions of the direct target genes of miR-30c (including PAI-1 in both blood and brain, elF2α and caspase-3 in the brain) induced by cerebral I/R injury were significantly decreased by IV miR-30c mimic treatment. Based on these exciting new findings from young adult mice, we propose the innovative hypothesis that miR-30c functions as a critical regulator of thrombo-inflammation and ER stress in the ischemic brain elicited by cerebral I/R injury, and thus targeting miR-30c represents a novel therapeutic approach for combating cerebral I/R injury. Following updated stroke Therapy Academic Industry Roundtable (STAIR) pre-clinical guidelines, we will test this hypothesis in aged male and female mice. Specifically, we will determine the efficacy and safety of IV miR-30c mimic as novel stroke therapeutics (Aim1). Using complementary approaches, i.e. the “gain-of-function” (miR- 30c mimic) and “loss-of-function” (anti-sense Morpholino oligos that are designed to specifically compete with miR-30c for binding sites of 3’UTR of each individual target gene and thus acts as a “target protector”), we will identify PAI-1 as a key molecular target of miR-30c in regulation of post-stroke thrombo-inflammation (Aim 2), and identify elF2α and caspase 3 as key molecular targets of miR-30c in regulation of post-stroke neuronal ER stress and neuronal cell death (Aim 3). The long-term goal of these studies is to evaluate if targeting miR-30c is a viable option for stroke therapy in both male and female older populations at high risk for stroke.

项目摘要/摘要 脑缺血/再灌注（I/R）损伤是治疗急性患者的主要挑战 缺血性静脉曲张（IV）目前没有有效的溶栓和血管内治疗 可用于治疗/预防脑I/R损伤的干预措施。 大脑中炎症反应（血栓炎症）和异常内质网（ER）应激 大脑I/R引起的重要性对次要的脑损伤和神经病学的贡献很重要 提案我们希望制定一种基于miRNA的新型治疗策略，以同时针对这些 大脑I/R R损伤的病理过程，不同的分子机制 miR-30c的表达在patiance和动物模型的许多病理条件下都涉及。 在预序研究中，我们表明miR-30c在血小板，脑膜片中高度表达 正常小鼠的皮质/海​​马神经元，但其水平随着年龄的增长而下降。 缺血性中风后明显降低大脑，并通过单静脉注射合成的miR-30c升高 miR-30c模仿可显着防止脑I/R损伤。 miR-30c的直接靶基因（血液和脑中的含有PAI-1，脑中的ELF2α和caspase-3） 静脉I-30C模拟治疗可显着降低脑I/R损伤 激动人心的成年小鼠的新发现，我们提出了一种创新的假设，即miR-30c的作用与 脑I/R损伤引起的缺血性大脑中血栓炎和ER应力的关键调节剂 因此，靶向miR-30c代表了打击脑I/R损伤的新型武器。 更新的中风疗法学术行业圆桌会议（楼梯）临床前指南，我们将测试TRIS 在老年男性和雌性小鼠中的假设。 模仿新型中风治疗（AIM1）。 30c模拟）和“功能丧失” miR-30c用于结合每个靶基因的3'UTR，因此起作用为A），我们将 将PAI-1识别为miR-30c的关键分子靶标，以调节势后thrombo炎症（AIM 2），，AIM 2）， 并识别ElfyElf2α和caspase 3为miR-30c的关键分子靶标，以调节触摸后神经元的调节 压力和神经元细胞死亡（AIM 3）。 男性和女性老年人的中风的可行选择，中风风险很高。