ISAC Award Program Application Concept

Targeting kidney proximal tubule cell dedifferentiation in CKD
Craig Brooks   (Nashville, TN)
In chronic kidney disease (CKD), excess extracellular matrix (ECM) production, termed fibrosis, is a source of continuous injury. Fibrosis expansion leads to deterioration of kidney structure and function, culminating in end stage renal disease. While fibroblasts are the main source of ECM production, the driving force behind the fibrotic expansion is signaling from injured and dedifferentiated tubule epithelial cells (TEC). Our recent studies have demonstrated that kidney fibrosis shares many characteristics with growing tumors. Proto-oncogenes (p53, cyclin G1, CDK5, and etc) are key regulators of TEC profibrotic response. The growth of both tumors and kidney fibrosis is driven by maladaptively dedifferentiated cells that recruit and activate fibroblasts. In both diseases, fibroblasts proliferate and lay down extracellular matrix to rearrange the surrounding environment. Ultimately, if left unchecked, the growing fibrotic area and dysregulated proliferation will destroy the organ. Based on these observations, we propose CKD should be recharacterized as a consequence of non-malignant tumor growth. Reimagining kidney fibrosis as a growing tumor shifts the idea of how to treat the disease, suggesting CKD should be treated more aggressively. We propose that simultaneously targeting dedifferentiated TECs and myofibroblasts for elimination will stop CKD progression in the short and long terms, similar to cancer therapies. To prove the concept that elimination of maladaptively dedifferentiated TECs and myofibroblasts is a potential therapeutic to treat CKD, we will breed mice expressing the floxed human diphtheria toxin receptor (DTR) with mice expressing a tamoxifen inducible Cre recombinase under control of a TEC dedifferentiation gene promotor (Sox9) to eliminate dedifferentiated TECs in the chronic phase of kidney injury. We will then test whether eliminating the dedifferentiated PTCs alone or in combination with anti-proliferative chemotherapeutic drugs will prevent CKD progression. Our proof-of-concept findings will upend the current dogma by demonstrating that instead of trying to save or heal dedifferentiated TECs in CKD, the best current treatment option is to eliminate the problematic cells (TECs and myofibroblasts). This finding will demonstrate that it is possible to halt CKD progression and will likely open up a new field of repurposing cancer therapeutics to treat CKD, potentially producing novel therapeutics in short order.
Data for this report has not yet been released.

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