Harnessing stem cells and synthetic gene circuits to repair glomerular injury

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More than 15% of U.S. adults suffer from chronic kidney disease (CKD) and end-stage kidney disease (ESKD), which costs more than $81 billion in annual Medicare expenditures (almost double the entire NIH budget). Worldwide, there are more patients with CKD (850 million) than diabetes (422 million), COVID-19 disease (584 million, August 2022), cancer (42 million), HIV/AIDS (36.7 million), and Parkinson’s disease (10 million). Compounding the overwhelming burden of CKD, there are no therapies proven to reverse or even halt CKD progression to ESKD. Currently, the only treatment options for ESKD are dialysis and kidney transplantation. Because survival on dialysis is limited (five to ten years), and access to organ transplantation is insufficient, many patients die while waiting for a kidney transplant. Innovative, high-risk, high-reward approaches, such as those proposed here, are needed to improve kidney disease outcomes. Progress in kidney medicine is limited by the lack of experimental models that can accurately recapitulate human physiological responses. Due to divergent developmental and functional molecular mechanisms, animal models often fail to faithfully replicate human kidney biology and drug responses. To address this significant limitation, research in my lab integrates technologies at the interface of human stem cell biology, organoids and organs-on-chips or tissue-chip microphysiological systems, and cellular reprogramming to help advance molecular-level understanding of kidney disease mechanisms and discover new therapeutic strategies. The most severe forms of kidney disease involve injury and irreversible damage to podocytes -- the terminally differentiated epithelial cells that encase glomerular capillaries and function together with the endothelium to regulate the removal of toxins and waste from the blood. Because podocytes do not replenish themselves naturally, damage to these cells (through drug side effects, viral infections, genetic and environmental risk factors) often progresses to CKD and organ failure. There is an urgent need to develop new tools to ease the social, economic, and clinical burden of kidney disease. This proposal offers strategies to repair and regenerate damaged kidney tissues by leveraging our stem cell-derived kidney models to uncover tunable molecular targets for cell-type-specific sensing and stimulation of tissue repair processes. We will extend these findings to engineer synthetic molecular circuits for autonomous repair of damaged podocytes and glomerular tissues to help restore the kidney’s blood filtration function. Consistent with the goals of the NIH Director’s New Innovator Award program, this proposal presents an unconventional approach to kidney biology and medicine by providing new avenues to repair and regenerate injured kidney tissues with biological relevance to humans. Accomplishing the goals of this study will represent a paradigm shift in research and clinical nephrology, providing opportunities to develop cell-autonomous strategies as new therapeutic modalities for kidney disease. Thus, the risks are justified by the magnitude of potential impact.