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

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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.