Mitochondrial RNA as a proinflammatory mediator

线粒体 RNA 作为促炎介质

• 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
• 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

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，被认为与大多数主要原因有关 在美国，死亡率很高，相关成本也很高。新的见解，以更好地了解其 因此，病因学、检测和预防在卫生保健中具有重要意义。这在一定程度上已经实现。 通过最近发现的促炎DAMP，包括线粒体DNA（mtDNA）。然而，在这方面， 关于另一种主要的线粒体核酸，即mtDNA的促炎作用，人们知之甚少。在这里， 我们建议通过扩展我们最近的mtDNA研究和评估治疗靶点来填补这一空白。这些 这些研究是以前关于mtDNA免疫刺激的少量文献的主要扩展，并提供了新的 深入了解天然和氧化的mtDNA在炎症中的作用，因为它们不适当地释放， 细胞质和细胞外环境包括血液。具体来说，我们建议测试假设， 天然和氧化的mtDNA是具有诊断和治疗潜力的重要炎症介质。 在这里，我们将描述线粒体RNA的促炎活性的机制基础 （mtDNA）;确定氧化对mtDNA免疫刺激的机制作用;并评估 免疫刺激活性和人类血浆中mtDNA的相关结构形式。总体目标是 更好地了解天然和氧化形式的mtDNA在炎症中的作用，并最终 利用这些信息来诊断和治疗过量的mtDNA释放相关的炎症， 病理学