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。的确有 越来越多的证据表明炎症对脑出血的预后有贡献，但潜在的机制仍然存在 很大程度上是未知的。ICH对少数民族/种族少数群体和年轻人的影响不成比例。我们的初步数据 证实了有报道称，脑出血幸存者有很高的进行性认知功能减退，这似乎是由 侵袭性脑出血炎症反应。胞外体是从细胞释放到细胞内的胞外小泡。 循环血液；通过分析从神经元和小胶质细胞释放的外切体，脑特异性炎症 可以通过检测循环血浆来评估病理生理学。外切体运输微小RNA(MiRNA)， 是基因表达的强大调节者。在我们的初步研究中，出现了三种炎症介质 在脑出血后炎症中尤为突出，并有望在一项更大的研究中进行额外的分析：单核细胞， 白介素8(IL-8)和miRNA(MiR)-181a。我们建议顶石(中央性和外周性卒中 外周体炎)研究，将招募250名先前招募到玫瑰草坪的脑出血患者 研究(中风的康复，神经影像的纵向评估，R01NS120493)。卡普斯通将 利用来自玫瑰草坪的血浆、外周血和功能/认知结果；连续的血浆和血液 样本将从基线、ICH后3个月和18个月开始分析。 通过以下目标，我们将实现我们的总体目标，即识别相关的转录生物标志物 有6个月的功能结局和长期进行性认知能力下降。具体目标1将决定 神经元和小胶质细胞来源的外体中的miRNA与6个月的功能结局和长期的 进行性认知功能下降(脑出血后约24个月)。我们假设在神经元中miR-181a减少 而小胶质细胞外切体会预测较差的近期功能结局和较大的长期认知能力 拒绝。特异性目标2将测定外周血白细胞中与6个月相关的mRNA和miRNA 功能结局与长期进行性认知功能下降(脑出血后约24个月)。我们假设 MiR-181a降低，CXCL8和IL-8升高将预示更差的功能结局和更长的长期 认知能力下降。特指目标3将探索中枢和外周炎症之间的相互作用 脑出血后的处理。我们假设在神经元和小胶质细胞来源的外体中miR-181a减少 将与外周血白细胞中CXCL8和IL-8的升高有关。 脑出血后炎症是脑源性和全身性病理的相互作用，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 血浆中的外切体(即脑源性)，Capstone试图提供关于这些的实质性见解 炎症过程。这项研究还解决了NINDS恢复、成像和血管方面的优先事项 认知障碍。