Lupus nephritis: novel insights in the pathogenesis and treatment - overall abstract little is known about the pathogenesis of lupus nephritis (LN), particularly as IT relates to the initiation and…

Lupus nephritis: novel insights in the pathogenesis and treatment - overall abstract little is known about the pathogenesis of lupus nephritis (LN), particularly as IT relates to the initiation and propagation of the inflammatory response which accounts for the development or end stage renal disease. LN may complicate up to two thirds of patients with systemic lupus erythematosus with higher rates commonly seen among minorities and children. Besides the needle kidney biopsy, we lack tools that reflect tissue pathology with fidelity. Although two drugs have been recently approved to treat patients with LN, all treatment protocols involve systemic administration of drugs or biologics which are laden with side effects and limited clinical efficacy. Ample evidence has revealed that kidney resident cells and newly formed high endothelial venules in the presence of an autoinflammatory environment, upregulate molecules which account for the ensuing inflammation and cell damage, while in their absence, kidney damage is averted. These molecular changes can be recorded in parallel in podocytes and tubular epithelial cells in the urine. This proposal will test the hypothesis that interaction of constituents of the immune system with kidney resident cells and the ectopically formed high endothelial venules, determines the development of inflammation and injury in the setting of LN. Corollaries of this hypothesis are that kidney resident cells can serve as gateways for the administration of targeted therapeutics for the treatment of LN and that kidney tissue pathology can be recorded with high fidelity in the urine cells of patients with LN. There are 2 projects in this proposal: 1) interplay between autoimmune effectors and kidney resident cells in lupus nephritis and 2) newly formed high endothelial cells in the kidney- pathogenesis and implications in lupus nephritis. The proposal will be supported by 3 cores: the administrative core will be responsible for regulatory compliance, budget management, scheduling meetings. The nanoparticle immune delivery core will be responsible for the construction of nanoparticles loaded with drugs and biologics and tagged with antibodies for cell-specific delivery. The single cell, spatial transcriptomics and bioinformatics core will perform single cell transcriptomics studies and will provide statistical and bioinformatics support. This proposal through extensive synergistic plans between the project leaders brings forward novel and significant elements in the study of the pathogenesis, treatment and biomarker development in patients with LN.