CAPSTONE: Central And Peripheral STrOke inflammatioN with Exosomes

顶点：外泌体引起的中枢和外周中风炎症

• 批准号: 10502776
• 负责人: Kyle Brendan Walsh
• 金额: $ 77.63万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-19 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10502776
• 关键词: Address; Affect; Anti-Inflammatory Agents; Biological Markers; Black Populations; Blood; Blood Circulation; Blood Tests; Blood specimen; Brain; Brain Injuries; Cells; Cerebral hemisphere hemorrhage; Clinical; Clinical Research; Cognitive; Data; Data Set; Death Rate; Development; Disabled Persons; Enrollment; Ethnic Origin; Evaluation; Extracellular Space; Female; Functional disorder; Gene Expression; Gene Proteins; Genes; Goals; Hemorrhage; Hispanic Populations; Human; IL8 gene; Image; Impaired cognition; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin-8; Investigation; Leukocytes; Literature; Measures; Messenger RNA; MicroRNAs; Microglia; Molecular; National Institute of Neurological Disorders and Stroke; Neurons; Outcome; Pathology; Patient-Focused Outcomes; Patients; Peripheral; Persons; Phenotype; Plasma; Process; Proteomics; RNA; Race; Recovery; Regulator Genes; Reporting; Research; Sample Size; Sampling; Science; Severities; Stroke; Survivors; Testing; Untranslated RNA; Vascular Cognitive Impairment; cognitive recovery; cohort; cytokine; differential expression; disability; exosome; extracellular vesicles; follow-up; functional outcomes; insight; mRNA sequencing; male; monocyte; mortality; nervous system disorder; neuroimaging; peripheral blood; preclinical study; racial and ethnic; racial diversity; racial minority; recruit; sex; stroke recovery; study population; systemic inflammatory response; transcriptome sequencing; transcriptomics; vesicular release

Project Summary/Abstract Intracerebral hemorrhage (ICH) is a severe neurological disorder with no proven treatment. There is increasing evidence that inflammation contributes to ICH outcomes, but the underlying mechanisms remain largely unknown. ICH disproportionately affects ethnic/racial minorities and young people. Our preliminary data confirms reports that ICH survivors have a high rate of progressive cognitive decline, plausibly initiated by the aggressive ICH inflammatory response. Exosomes are extracellular vesicles released from cells into the circulating blood; by analyzing exosomes released from neurons and microglia, brain-specific inflammatory pathophysiology can be assessed by testing circulating plasma. Exosomes transport microRNA (miRNA) that are powerful regulators of gene expression. In our preliminary studies, three inflammatory mediators emerged as particularly salient in post-ICH inflammation and promising for additional analysis in a larger study: monocytes, interleukin-8 (IL-8), and miRNA (miR)-181a. We propose the CAPSTONE (Central And Peripheral STrOke inflammatioN with Exosomes) study that will enroll 250 ICH subjects previously recruited into the ROSE-LAWN study (Recovery of StrokE, Longitudinal Assessment With Neuroimaging, R01NS120493). CAPSTONE will utilize plasma, peripheral blood, and functional/cognitive outcomes from ROSE-LAWN; serial plasma and blood samples will be analyzed from baseline, three months, and 18 months after ICH. Through the following aims, we will pursue our overall goal to identify transcriptomic biomarkers associated with six-month functional outcome and long-term progressive cognitive decline. Specific Aim 1 will determine miRNA in neuronal- and microglial-derived exosomes that correlate with six-month functional outcome and long- term progressive cognitive decline (~24 months after ICH). We hypothesize that decreased miR-181a in neuronal and microglial exosomes will predict worse near-term functional outcome and greater long-term cognitive decline. Specific Aim 2 will determine mRNA and miRNA in peripheral leukocytes that correlate with six-month functional outcome and long-term progressive cognitive decline (~24 months after ICH). We hypothesize that decreased miR-181a and increased CXCL8 and IL-8 will predict worse functional outcome and greater long-term cognitive decline. Specific Aim 3 will explore the interactions between central and peripheral inflammatory processes post-ICH. We hypothesize that decreased miR-181a in neuronal- and microglial-derived exosomes will be associated with increased CXCL8 and IL-8 from peripheral leukocytes. Post-ICH inflammation is an interplay of both brain-derived and systemic pathology, but the associated molecular mechanisms remain poorly understood. By analyzing circulating blood (i.e., systemic) and cell-specific exosomes in plasma (i.e., brain derived), CAPSTONE seeks to provide substantial insight regarding these inflammatory processes. This research also addresses the NINDS priorities of recovery, imaging, and vascular cognitive impairment.

项目摘要/摘要 脑内出血（ICH）是一种严重的神经系统疾病，没有经过良好治疗。有 越来越多的证据表明炎症会导致ICH结果，但潜在的机制仍然存在 在很大程度上未知。 ICH不成比例地影响种族/种族少数群体和年轻人。我们的初步数据 确认报告说，ICH幸存者的进行性认知能力下降率很高，这是由 激进的ICH炎症反应。外泌体是细胞外囊泡从细胞释放到 循环血；通过分析神经元和小胶质细胞释放的外泌体，脑特异性炎症 可以通过测试循环血浆来评估病理生理学。外泌体转运microRNA（miRNA） 是基因表达的强大调节剂。在我们的初步研究中，出现了三个炎症介质 在较大的研究中特别有望进行其他分析：单核细胞，尤其有望进行其他分析： 白介素8（IL-8）和miRNA（mir）-181a。我们提出了顶峰（中央和外围卒中 外泌体的炎症）研究，将招募250名先前招募到玫瑰的ICH受试者 研究（中风的恢复，纵向评估，神经影像学，R01NS120493）。 Capstone Will 利用血浆，外周血和玫瑰玫瑰的功能/认知结果；系列血浆和血液 样本将从基线，三个月和18个月后进行分析。 通过以下目标，我们将追求我们的整体目标，以识别相关的转录组生物标志物 六个月的功能结果和长期渐进认知能力下降。具体目标1将决定 神经元和小胶质细胞衍生的外泌体中的miRNA，与六个月的功能结果相关，长长 术语进行性认知下降（ICH后24个月）。我们假设神经元中的miR-181a降低 小胶质细胞外泌体将预测近期功能结果和更大的长期认知能力更糟 衰退。特定的目标2将确定与六个月相关的外周白细胞中的mRNA和miRNA 功能结果和长期渐进认知能力下降（ICH后24个月）。我们假设这一点 miR-181a降低，CXCL8和IL-8的增加将预测功能性较差，并且长期更长 认知能力下降。特定的目标3将探索中央炎症和外围炎症之间的相互作用 流程后的。我们假设在神经元和小胶质细胞衍生的外泌体中miR-181a降低 将与周围白细胞的CXCL8和IL-8增加有关。 伊奇后的炎症是脑衍生和系统病理的相互作用，但相关的 分子机制仍然很少理解。通过分析循环血液（即全身性）和细胞特异性 血浆中的外泌体（即脑衍生），Capstone试图就这些提供实质性的见解 炎症过程。这项研究还涉及恢复，成像和血管的NIND优先级 认知障碍。