A quarter to more than one half of the ~ one million people with systemic lupus erythematosus (SLE) in North America will either present with lupus nephritis (LN) or will develop LN at some point in the course of their disease. The available treatment tools include immunosuppressive drugs and the recently added Benlysta and the calcineurin inhibitor, voclosporin. They are not specific drugs with the first three causing major side effects, whereas, the last two have a small, albeit desirable, clinical benefit. Better understanding of the pathogenesis of LN will advance our progress towards the development of reliable biomarkers and approaches to treat patients in a precise manner. Early studies have indicated that kidney resident cells (podocytes, mesangial and tubular epithelial cells) when exposed to the autoinflammatory environment that is prevalent in patients with LN, they upregulate immunomodulatory molecules including a serine/threonine kinase IV (CaMK4) and interleukin 23 receptor (IL-23R) which enable kidney inflammation and damage. When kidney resident cells lack any of these molecules, inflammation is averted. Importantly, urine podocytes and tubular epithelial cells present molecular abnormalities which reflect those in the kidney tissue. In this project, the hypothesis will be tested that in response to peripheral autoimmune elements, kidney resident cells undergo molecular changes which are requisite for the development of kidney inflammation and injury. The hypothesis will be tested in three sets of experiments. In the first it will be demonstrated that CaMK4 and IL-23R in podocytes are requisite for the development off LN; in the second it will be demonstrated that upregulation of CaMK4 and IL- 23R in tumular epithelial cells alters their metabolic profile and enables them to produce chemokines that attract inflammatory cells leading to LN; in the third a pilot clinical study will be performed to first demonstrate that upregulation of CaMK4 and IL-23R in urine cells reflects kidney tissue pathology, and second, that the recording of these molecules in the urine can predict the development of LN in patients with SLE. The project will use a number of novel tools availed in the laboratory and by the cores (single cell and spatial transcriptomics and nanoparticle delivery of medicine to kidney resident cells) of this project program grant along with conditionally knock out mice and a well-established lupus cohort. The project addresses directly three unmet needs in LN: understanding of pathogenesis, development of precision treatment approaches and high-fidelity biomarkers.