PROJECT SUMMARY: Treatment paradigms for kidney disease have been largely stagnant for decades. However, new technologies in stem cell biology are opening the doors to novel diagnostic and therapeutic modalities. The PI is an MD/PhD trainee at Northwestern University whose goal is to use this F30 NRSA to take the first steps toward developing a career niche in renal medicine and nanotechnology. This training program combines complementary scientific and career development pathways for the aspiring academic physician- scientist to elucidate mechanisms of kidney disease and develop novel nephrotherapeutics that will initiate his career trajectory. Specifically, this project proposes to use new stem cell technologies, already available in the sponsor's laboratory, to generate human multicellular renal organoids that orchestrate podocytes, endothelial and epithelial cells to form glomerular, vascular and tubular compartments. While renal organoid formation recapitulates the kidney's developmental process, their use in modeling genetic diseases (e.g., such as polycystic kidney disease) has been well established. However, the ability of renal organoids to model acquired diseases of the kidney has been largely ignored. To address this deficit within the field, this proposal centers on investigating renal pathologies due to circulating factors that lead to kidney injury and ultimately disease. To investigate and generate this needed knowledge, the broad hypothesis of this investigation is that 3D kidney organoids can be harnessed to develop disease models as testbeds for novel therapeutics for known mechanisms of acquired kidney injury (such as drug induced nephrotoxicity) AND may be used to screen for unknown mediators of acquired kidney diseases. To investigate this hypothesis and provide a proof-of-concept, the PI trainee proposes two aims: Aim 1 incubates organoids with a nephrotoxic drug to model a known mechanism of kidney injury and tests the ability to attenuate injury using a novel nanotherapeutic developed and published by the PI's sponsors. Aim 2 screens for a suspected circulating factor by incubating organoids in the presence of patient-derived plasma from an already established bank derived from patients with renal dysfunction. The research strategy contained in this application lays out a methodical and rigorous approach to investigate the impact of kidney organoids on renal medicine and to determine the extent to which organoids may be fine-tuned to recapitulate human kidney disease and test novel therapeutics in vitro. To complement the research program and enable the PI to embark on a career in renal nanomedicine, this proposal leverages the support of diverse mentors and resources in kidney therapeutics, pathophysiology, organoid biology, biomedical engineering, and nanotechnology. Ultimately, this NRSA research and training plan provides for a rigorous program to create a new career niche in renal nanomedicine for a lifelong career uncovering mechanisms of kidney disease and attenuating abnormal pathways with novel therapeutic agents.

PROJECT NARRATIVE: Medicare spending on acute, chronic, and end-stage kidney disease amounts to more than 100 billion dollars annually. Animal models of kidney disease often fail to translate to humans and are neither cost- nor time-effective to screen libraries of potential therapeutics. This project will investigate the impact of multicellular kidney organoids on renal medicine and determine whether kidney organoids may be fine-tuned to be in vitro representatives of human disease for the purposes of 1) developing therapeutics to protect against known toxins and 2) serving as a readout to screen for unknown “perfusable” factors that lead to kidney disease.