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: 10668530
• 负责人: Kyle Brendan Walsh
• 金额: $ 76.08万
• 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/10668530
• 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 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.

项目总结/摘要 脑出血（ICH）是一种严重的神经系统疾病，目前尚无有效的治疗方法。有 越来越多的证据表明炎症有助于ICH结局，但潜在机制仍然存在 大部分未知。非物质文化遗产对少数民族/种族和年轻人的影响不成比例。我们的初步数据 证实了ICH幸存者进行性认知功能下降的发生率很高，可能是由脑出血引起的。 侵袭性ICH炎症反应。外来体是从细胞释放到细胞外的细胞外囊泡。 循环血液;通过分析神经元和小胶质细胞释放的外泌体，脑特异性炎症反应 病理生理学可以通过测试循环血浆来评估。外泌体转运microRNA（miRNA）， 是基因表达的强大调节器。在我们的初步研究中，出现了三种炎症介质 在脑出血后炎症中特别突出，并有望在更大的研究中进行额外的分析：单核细胞， 白细胞介素-8（IL-8）和miRNA（miR）-181 a。我们提出了CAPSTONE（Central And Peripheral Stroke 该研究将招募250名先前招募到ROSE-LAWN的ICH受试者 研究（卒中恢复，神经影像学纵向评估，R 01 NS 120493）。CAPSTONE将 利用来自ROSE-LAWN的血浆、外周血和功能/认知结果;系列血浆和血液 将从基线、ICH后3个月和18个月分析样本。 通过以下目标，我们将追求我们的总体目标，以确定转录组生物标志物相关的 六个月的功能结果和长期进行性认知下降。具体目标1将决定 神经元和小胶质细胞来源的外泌体中的miRNA与6个月的功能结果和长期的 长期进行性认知功能下降（ICH后约24个月）。我们假设，在神经元中减少miR-181 a， 小胶质细胞外泌体将预测更差的近期功能结果和更大的长期认知功能。 下降特异性目的2将确定外周血白细胞中与6个月的免疫相关的mRNA和miRNA。 功能结局和长期进行性认知下降（ICH后约24个月）。我们假设 miR-181 a减少和CXCL 8和IL-8增加将预测更差的功能结局和更大的长期预后。 认知能力下降具体目标3将探讨中枢和外周炎症之间的相互作用， ICH后处理。我们假设，神经元和小胶质细胞来源的外泌体中miR-181 a的减少 将与来自外周白细胞的CXCL 8和IL-8的增加相关。 ICH后炎症是脑源性和全身性病理学的相互作用，但相关的 分子机制仍然知之甚少。通过分析循环血液（即，全身性）和细胞特异性 血浆中的外来体（即，大脑衍生），CAPSTONE旨在提供有关这些的实质性见解 炎症过程。这项研究还涉及NINDS的恢复，成像和血管的优先事项 认知障碍