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，并且被认为是大多数主要原因今天美国的死亡人数很高，相关费用也很高。更好地理解其的新见解因此，病因学、检测和预防对于卫生保健至关重要。这已经部分实现最近发现促炎症 DAMP，包括线粒体 DNA (mtDNA)。然而，人们对另一种主要线粒体核酸（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 mRNA 研究和评估治疗靶点来填补这一空白。这些研究是先前关于 mRNA 免疫刺激的小文献的主要延伸，并提供了新的深入了解天然和氧化 mRNA 在炎症中的作用，因为它们不适当地释放到细胞质和细胞外环境，包括血液。具体来说，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，我们将描述线粒体 RNA 促炎活性的机制基础（线粒体RNA）；确定氧化对 mRNA 免疫刺激的机制影响；并评估人血浆中 mtRNA 的免疫刺激活性和相关结构形式。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，并最终利用这些信息来诊断和治疗与 mtRNA 过度释放相关的炎症病理学。