Altered High-Density Lipoprotein function in Patients with Idiopathic Inflammatory Myopathies

项目总结/摘要 血管内皮的损伤是心血管疾病的原因，心血管疾病是心血管疾病的主要原因。 自身免疫性疾病患者的死亡率。在特发性炎性肌病（IIM）中，这一过程是 特别相关的是，血管损伤与疾病发病机制及其相关的 主要器官并发症，间质性肺病（IIM-ILD）。然而，正在进行的 目前对IIM中的内皮活化和血管损伤还没有很好的了解。拟议研究 通过以下方式解决了关于IIM和IIM-ILD中血管损伤发病机制的关键知识缺口： 研究功能障碍性高密度脂蛋白介导的血管损伤永久化的新机制 脂蛋白（HDL）。HDL通常保护血管内皮免受损伤，但在某些炎症条件下， HDL可能会失去其抗炎特性，成为一种功能失调的促炎颗粒 促进内皮细胞损伤我们最近的研究表明，高密度脂蛋白和 IIM患者的HDL相关抗氧化酶对氧磷酶-1（PON 1）活性受损， 与更活跃的疾病相关。肠道微生物组已显示出与HDL的强烈关联， 影响心血管和肺部健康。我们对IIM和对照组肠道微生物组的初步结果 显示微生物组成和PON 1活性之间联系。我们假设高密度脂蛋白的变化- 相关的酶和蛋白质，促炎生物活性介质（BLM）和肠道微生物组结果 在功能失调的HDL中，导致血管内皮损伤的永久化，并最终增加IIM 疾病负担。我们将使用纵向IIM队列和HDL功能的全面评估， 研究以下具体目标：（1）评估异常HDL功能与 血管病变;（2）确定异常HDL功能随时间的变化是否与疾病相关 负担;和（3）检查肠道微生物组与HDL功能和疾病负担的关联。项目 将在加州洛杉矶大学（UCLA）进行，并得到多学科的支持。 由国家认可的专家组成的导师团队，以及一个主要学术机构的众多资源 该机构提供的服务包括研究生课程、核心设施和职业发展研讨会。完成 拟议的项目和培训计划将促进以下领域的高级培训：（1）微生物组研究 设计、数据收集、排序和分析;（2）实验室技术和统计分析方法 复杂的生物标志物组;和（3）IIM中的疾病结局指标，包括定量成像评分 IIM-ILD系统。这些方面的培训将为实现我的长期目标奠定基础， 独立的医生科学家结合临床，实验和计算方法来检测 影响疾病相关血管损伤的独特微生物和脂质功能特征，以识别 新的治疗靶点，可以改善包括IIM在内的自身免疫性疾病患者的生活。

PROJECT SUMMARY/ABSTRACT Damage to the vascular endothelium is responsible for cardiovascular disease, which is the leading cause of mortality in patients with autoimmune diseases. In idiopathic inflammatory myopathies (IIM), this process is particularly relevant as vascular damage is implicated in the disease pathogenesis as well as its associated major organ complication, interstitial lung disease (IIM-ILD). However, the precise mechanisms of ongoing endothelial activation and vascular damage in IIM are currently not well understood. The proposed research addresses a critical knowledge gap regarding the pathogenesis of vascular injury in IIM and IIM-ILD by investigating a novel mechanism for perpetuation of vascular damage mediated by dysfunctional high-density lipoproteins (HDL). HDL normally protects vascular endothelium from damage, but under certain inflammatory states, HDL may lose its anti-inflammatory properties and become a dysfunctional, pro-inflammatory particle that promotes endothelial cell damage. Our recent work demonstrates that the antioxidant function of HDL and HDL-associated antioxidant enzyme paraoxonase-1(PON1) activity are impaired in patients with IIM, and correlate with more active disease. The gut microbiome has shown strong associations with HDL and is known to impact cardiovascular and lung health. Our preliminary results of the gut microbiome in IIM and controls show a link between microbial composition and PON1 activity. We hypothesize that changes in HDL- associated enzymes and proteins, pro-inflammatory bioactive mediators (BLM) and the gut microbiome result in dysfunctional HDL, leading to the perpetuation of vascular endothelial damage and ultimately increased IIM disease burden. We will use a longitudinal IIM cohort and comprehensive assessments of HDL function to study the following specific aims: (1) evaluate the association between abnormal HDL function and vasculopathy; (2) determine whether changes in abnormal HDL function over time correlate with disease burden; and (3) examine the association of gut microbiome with HDL function and disease burden. The project will be conducted at the University of California Los Angeles (UCLA) with the support of a multidisciplinary team of mentors comprised of nationally recognized experts, and numerous resources of a major academic institution, including graduate courses, core facilities, and career development seminars. Completion of the proposed project and training plan will facilitate advanced training in the following areas: (1) microbiome study design, data collection sequencing and analysis; (2) laboratory techniques and statistical analysis methods for complex biomarker panels; and (3) disease outcome measures in IIM, including a quantitative imaging scoring system in IIM-ILD. Training in these areas will provide a foundation to achieve my long-term goal, to be an independent physician-scientist combining clinical, experimental and computational approaches to detect unique microbial and lipid function signatures that impact disease-related vascular damage, in order to identify novel therapeutic targets that may improve the lives of patients with autoimmune diseases including IIM.