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

特发性炎症性肌病患者高密度脂蛋白功能的改变

基本信息

批准号：
10739224
负责人：
Sangmee Bae
金额：
$ 18.2万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10739224
关键词：
Acceleration Address Affect Anti-Inflammatory Agents Antibodies Antioxidants Apolipoprotein A-I Area Arylesterase Atherosclerosis Autoimmune Diseases Blood Vessels California Cardiopulmonary Cardiovascular Diseases Cholesterol Clinical Complex Complication Core Facility Creatine Kinase Data Data Collection Dermatomyositis Dietary Intervention Disease Disease Outcome Endothelial Cells Endothelium Enzymes Foundations Goals High Density Lipoproteins Idiopathic Inflammatory Myopathies Impairment Inflammatory Institution Interstitial Lung Diseases Knowledge Laboratories Link Lipid Peroxides Lipids Longitudinal cohort Los Angeles Low-Density Lipoproteins Measures Mediating Mediator Mentors Methods Modification Neutrophil Infiltration Organ Outcome Measure Oxidative Stress Pathogenesis Patients Peroxidases Phospholipids Physicians Probiotics Process Progressive Disease Property Proteins Research Research Design Resources Rheumatoid Arthritis Sampling Scientist Severities Standardization Statistical Data Interpretation Subgroup System Systemic Lupus Erythematosus Taxonomy Techniques Testing Therapeutic immunosuppression Time Training Universities Vascular Diseases Vascular Endothelium Work antioxidant enzyme biomarker panel burden of illness cardiovascular health career development cell injury chest computed tomography circulating biomarkers cohort disorder control endothelial dysfunction fecal microbiome fecal transplantation follow-up gut microbiome improved lipid mediator lung health microbial microbial composition microbiome microbiome research microbiota mortality mouse model multidisciplinary new therapeutic target novel novel therapeutics oxidation particle peptidomimetics prevent pulmonary vascular disorder pulmonary vascular permeability quantitative imaging therapeutic candidate therapeutic target ultrasound vascular injury

项目摘要

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.

项目总结/文摘