Small RNAs and risk of rheumatoid arthritis

小RNA与类风湿性关节炎的风险

• 批准号: 10569502
• 负责人: Michelle Jane Ormseth
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569502
• 关键词: 2' -Deoxythymidine; Affect; Autoimmune Diseases; Autoimmunity; Bacteria; Basic Science; Bioinformatics; Biological Assay; Biological Markers; Chronic; Clinical; Clinical Data; Data; Department of Defense; Development; Diagnosis; Disease; Disease Marker; Disease remission; Early Intervention; Early treatment; Etiology; Feces; First Degree Relative; Goals; Hepatitis C Therapy; Human; Human Genome; In Vitro; Individual; Inflammatory; Interferons; Length; Link; Malignant Neoplasms; Maps; Measures; Mediator; Membrane; Messenger RNA; MicroRNAs; Microbe; Nucleotides; Onset of illness; Pathway interactions; Patient Care; Patients; Pharmaceutical Preparations; Phase; Plasma; Prediction of Response to Therapy; RNA; RNA marker; Regulator Genes; Reporter Genes; Research; Rheumatoid Arthritis; Risk; Role; Sampling; Serology; Serum; Shotguns; Site; Small RNA; Specimen; Structure; Testing; Time; Transfer RNA; Translating; Translations; Untranslated RNA; Validation; Vesicle; Veterans; Virulence Factors; accurate diagnosis; aggressive therapy; antagonist; biomarker identification; cell type; clinical development; cohort; comparison control; disability; drug response prediction; gene function; high risk; human disease; human microbiota; immune function; improved; innovation; insight; machine learning method; member; metagenomic sequencing; microbial; microbial genome; microbiome; microbiome alteration; microbiome components; mimetics; mortality; next generation sequence data; novel marker; novel therapeutics; outcome prediction; pre-clinical; prevent; prospective; repository; response; screening; therapeutic RNA

Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease affecting nearly 1% of Veterans. Early and aggressive treatment of RA improves likelihood of remission and reduces disability. Therefore, biomarkers identifying patients with high likelihood of developing disease could stratify individuals who would benefit from early interventions aimed at preventing disease and reducing disability. Such biomarkers may also provide insight into disease mechanisms. Our overarching goal is to determine the role of human and microbial sRNAs in the development of RA. The rationale for the proposed research is that sRNAs are powerful gene regulators and markers of disease. We have found that circulating human and microbial sRNAs are altered in established RA patients compared to control subjects, are associated with disease measures and can alter inflammatory cellular pathways. Building on preliminary data, we will define circulating human (Aim 1) and microbial (Aim 2) sRNAs that predict development of RA and change between preclinical and clinical RA in discovery and validation cohorts and identify the function of predictive sRNAs. Aim 3 will determine if microbiome alterations in new-onset untreated RA are reflected in alterations in plasma microbial sRNAs. The proposed research is significant because it will help us to identify patients with high likelihood of developing RA, enabling us to identify individuals who would benefit from early interventions aimed at preventing disease and reducing disability. The proposal is innovative because it has the potential to revolutionize our understanding of markers and mechanisms underlying development of RA and our understanding of how the human microbiota can influence immune function. The study is high impact because it could identify fundamental, targetable mechanisms underlying developing RA and could lead to targeted sRNA therapeutics.

类风湿性关节炎（RA）是一种全身性炎症性自身免疫性疾病， 1%的退伍军人。早期和积极治疗RA可提高缓解的可能性， 减少残疾。因此，生物标志物识别具有高发展可能性的患者 疾病可能会使那些从旨在预防的早期干预中受益的人分层， 疾病和减少残疾。这些生物标志物也可以提供对疾病的洞察力 机制等 我们的首要目标是确定人类和微生物sRNAs在 RA的发展。这项研究的基本原理是，sRNA是一种强大的基因， 疾病的调节因子和标志物。我们发现循环中的人类和微生物sRNAs 与对照受试者相比，在确定的RA患者中发生了改变， 测量并改变炎症细胞通路。 在初步数据的基础上，我们将定义循环人类（目标1）和微生物（目标 2)预测RA发展以及临床前和临床RA之间变化的sRNAs， 发现和验证队列，并确定预测sRNA的功能。目标3将 确定新发未经治疗的RA中的微生物组改变是否反映在 血浆微生物sRNAs。 这项拟议中的研究意义重大，因为它将帮助我们识别高血压患者。 发展RA的可能性，使我们能够确定谁将受益于早期 旨在预防疾病和减少残疾的干预措施。该提案具有创新性 因为它有可能彻底改变我们对标记物和机制的理解 RA的潜在发展以及我们对人类微生物群如何影响 免疫功能这项研究具有很高的影响力，因为它可以确定基本的、有针对性的 这可能是发展RA的潜在机制，并可能导致靶向sRNA治疗。