Functional and Mechanistic Characterization of Lupus Susceptibility - PROJECT ABSTRACT Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by chronic inflammation and multi-organ involvement, leading to significant morbidity and mortality. SLE disproportionately affects women and individuals of Asian, African, and Hispanic descent, with a higher prevalence and severity compared to other populations. Despite advancements in research, the molecular mechanisms underlying SLE remain poorly understood, and current therapies are often insufficient due to clinical heterogeneity and unpredictable disease trajectories, underscoring the urgent need for novel interventions. Autophagy, a critical cellular mechanism for maintaining homeostasis, has emerged as a key player in SLE pathogenesis. Dysfunctional autophagy disrupts cellular processes, including lysosomal function, antigen presentation, and cytokine regulation, which are central to both immune and non-immune cell functions. While B and T cells have long been implicated in SLE, recent evidence highlights the role of classical monocytes (CD14++CD16−) and kidney-resident podocytes in driving disease progression. In SLE, monocytes exhibit impaired autophagy, resulting in defective phagocytosis and heightened production of pro-inflammatory cytokines, such as TNF-α and IL-6, fueling systemic inflammation. Similarly, podocytes rely on autophagy for maintaining structural integrity and glomerular filtration. Autophagy impairments in podocytes lead to cytoskeletal damage, apoptosis, and proteinuria, which are hallmark features of lupus nephritis. Genome-wide association studies (GWAS) have identified numerous SLE susceptibility loci; yet translating these findings into mechanistic insights remains challenging. Our study focuses on four key GWAS loci linked to genes involved in autophagy, lysosomal function, and apoptosis—pathways crucial for immune regulation and tissue homeostasis. We hypothesize that genetic variants within regulatory elements of these genes disrupt autophagy, exacerbating immune dysregulation and organ-specific damage in SLE. Aim 1 involves fine-mapping SLE susceptibility loci through imputation-based analysis of resequencing data from patients and controls. Functional variants will be prioritized using allele-specific expression, chromatin profiling, and 3D genome interaction data, followed by genotyping validation. Aim 2 evaluates the functional impact of these variants on autophagy and cellular processes using CRISPR-based modifications in immune (e.g., THP-1 monocytes) and non-immune (e.g., podocyte) cell models. Complementary studies in primary monocytes from SLE patients and healthy controls will validate findings. By elucidating the role of autophagy-related genetic variants in SLE, this research aims to uncover novel mechanisms of disease and identify therapeutic targets for precision medicine approaches.
