Mitochondrial RNA as a proinflammatory mediator

线粒体 RNA 作为促炎介质

基本信息

批准号：
10532080
负责人：
DANA R CRAWFORD
金额：
$ 8.15万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-14 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10532080
关键词：
Blood CCL2 gene Cause of Death Cells Cerebral Edema Chloroquine Cytoplasm Dendritic Cells Detection Diagnosis Diagnostic Disease Double-Stranded RNA Endosomes Etiology Foundations Future Goals Healthcare Human Immune response Immunization Immunologic Adjuvants In Vitro Inflammation Inflammation Mediators Inflammatory Injury Interferons Interleukin-10 Interleukin-6 Literature Mediator of activation protein Mitochondria Mitochondrial DNA Mitochondrial RNA Molecular Mus Nucleic Acids Oxidants Oxidation-Reduction Oxides Pathogenesis Pathology Pathway interactions Pattern Plasma Prevention RNA RNA Binding RNA Degradation Receptor Signaling Regulation Ribonuclease III Ribonucleases Role Signal Pathway Specificity Stroke TNF gene Testing Transforming Growth Factor beta United States comparative cost extracellular extracellular vesicles in vivo insight lung injury macrophage mouse model oxidation receptor receptor binding therapeutic target

项目摘要

Inflammation is implicated in a wide range of disorders and thought to be involved in most leading causes of death today in the United States with high associated costs. New insights into better understanding its etiology, detection and prevention are thus of major importance in health care. This has been achieved in part through the recent discovery of proinflammatory DAMPs, including mitochondrial DNA (mtDNA). However, little is known about the proinflammatory effects of the other major mitochondrial nucleic acid, mtRNA. Here, we propose to fill this gap by extending our recent mtRNA studies and assessing therapeutic targets. These studies are a major extension of a previously small literature on mtRNA immunostimulation, and provide new insights into the role of native and oxidized mtRNA in inflammation as a result of their inappropriate release to the cytoplasm and extracellular milieu including blood. Specifically, we propose to test the hypothesis that both native and oxidized mtRNAs are important inflammatory mediators with diagnostic and treatment potential. Here, we will characterize the mechanistic basis underlying the proinflammatory activity of mitochondrial RNA (mtRNA); determine the mechanistic effect of oxidation on mtRNA immunostimulation; and assess the immunostimulatory activity and associated structural forms of mtRNA in human plasma. The overall goal is to better understand the role of both native and oxidized forms of mtRNA in inflammation, and to eventually exploit this information toward the diagnosis and treatment of excessive mtRNA release-related inflammatory pathologies.

炎症与多种疾病有关，并被认为参与了大多数主要原因今天在美国的死亡人数高。对更好地理解其的新见解因此，病因，检测和预防在医疗保健中至关重要。这是部分实现的通过最近发现的促炎性潮湿，包括线粒体DNA（mtDNA）。然而，关于其他主要线粒体核酸MTRNA的促炎作用知之甚少。这里，我们建议通过扩展我们最近的MTRNA研究并评估治疗靶标来填补这一空白。这些研究是先前有关MTRNA免疫刺激的小文献的主要扩展，并提供了新的洞悉天然和氧化的mtRNA在炎症中的作用，因为它们的释放不当包括血液在内的细胞质和细胞外环境。具体而言，我们建议检验以下假设天然和氧化的MTRNA是具有诊断和治疗潜力的重要炎症介质。在这里，我们将表征线粒体RNA促炎活性的机械基础（mtrna）;确定氧化对MTRNA免疫刺激的机械作用；并评估人血浆中MTRNA的免疫刺激活性和相关的结构形式。总体目标是更好地了解天然和氧化形式的mtRNA在炎症中的作用，并最终利用此信息来诊断和治疗过度MTRNA释放相关炎症病理。