Uncovering novel mechanisms and potential therapeutic targets for IgA vasculitis through GWAS and systems-level analysis of regulatory networks.

PROJECT SUMMARY/ABSTRACT IgA vasculitis (IgAV) is the most common form of systemic vasculitis in children, characterized by IgA deposition in the small blood vessels of skin, kidney, gastrointestinal tract, and joints. Among patients with IgAV, 20%-55% have renal involvement. Renal manifestations include hematuria, proteinuria, and variable degree of kidney failure, leading to end stage renal disease in 2% cases. The exact pathogenesis of IgAV is currently unknown, and there are no targeted treatments for IgAV. This proposal aims at uncovering pathogenic mechanism of IgAV using human genetics and systems biology approaches. In Aim 1, we will use GWAS approach to discover novel genetic factors for IgAV, nominate candidate disease-causing genes, and investigate shared genetic determinants with other immune-mediated traits to facilitate drug repositioning. In Aim 2, we will study the global landscape of immune cell type-specific expression and splicing QTLs in IgAV, identify IgAV-specific genomic regulators for gene regulation, and intersection with GWAS loci to elucidate the functional consequences of IgAV risk alleles and further prioritize candidate casual genes. In Aim 3, we will identify the driver genes through reconstruction of disease context-specific and cell-type specific regulatory networks, and define causal genetic alternations acting upstream of the driver genes. This will allow us to define the pathogenetic pathways based on the prioritized driver genes and genetic alternations. Lastly, the prioritized pathogenetic drivers and variants will be tested against clinical data to facilitate translation of these findings into clinical benefits. In summary, the proposed research will provide new insights into the genetic determination and pathogenesis of IgAV,and will significantly contribute to the development of new and improved strategies to detect, treat, and prevent IgAV. My overarching career goal is to become an independent investigator with a focus on identifying therapeutic targets for immune-mediated kidney diseases through systems genetics analyses of population-level multi-omics data. During this 5-year K01 Career Development Award, I will expand my training in autoimmunity and precision medicine and to acquire the skills necessary to conduct state-of-the-art population-based systems genetics studies. In the last two years of the award, I will apply for R03 and R01 funding and transition to independence. To guide and support my research and training goals, I have assembled a multidisciplinary mentorship team of experts in Nephrology and Complex Traits Genetics (Dr. Kiryluk, primary mentor), Systems Biology (Dr. Califano, co-mentor), Statistical Genetics (Dr. Ionita-Laza, co-mentor), Molecular Genetics and Precision Medicine (Dr. Gharavi, Advisor), Human Autoimmunity (Dr. Winchester, Advisor), and Career Development (Dr. Rubin, Advisor). The research will be conducted at Columbia University, which will give me access to extensive research resources and training to help me successfully transition to independence.