Polycystic kidney disease (PKD) is a term applied to a group of inherited disorders characterized by the presence of cysts in the kidney although multiple organs are typically affected. Renal pathologies found in essentially all forms of PKD include increased fluid secretion, matrix remodeling, cellular proliferation, and apoptosis, with a altered differentiation of the epithelial cells lining the renal cysts. PKD represent conditions tht are inherited as either autosomal dominant (AD) or autosomal recessive traits. ADPKD occurs in 1-in-500 to 1-in-1000 individuals, primarily as a result of mutations in one of two genes, PKD1 or PKD2. These mutations drive a pathology which results in inactivation of AMPK and over-activation of mTOR and Wnt signaling pathways leading to inappropriate cellular proliferation of the epithelial cells lining the tubules of the nephron. At this time, there is no therapeutic intervention approved for halting PKD progression. Metabolic Solutions Development Company (MSDC; www.msdrx.com) is developing novel insulin sensitizing agents which interact with a newly identified mitochondrial target (mTOT, mitochondrial Target of the Thiazolidinediones) while sparing activation of the PPAR receptor. These agents have shown efficacy in Phase II clinical trials for type 2 diabetes and modulate carbon flow from pyruvate into the mitochondrial matrix on a tissue specific/metabolic demand basis. Modulation of mTOT by these compounds elicits changes in signaling pathways that include activation of AMPK and inhibition of mTOR and the Wnt signaling pathways in cell and animal models used in the diabetes development program. Since these changes in signaling pathways are in the opposite direction of that seen in PKD, MSDC evaluated the potential therapeutic use of these mTOT modulating insulin sensitizing agents in an animal PKD model and found that they reduced kidney and liver cyst volume. Furthermore, in an initial assessment of the ability of mTOT modulating agents to influence signaling pathways in human cystic epithelial cells derived from ADPKD patients, activation of AMPK was observed. Thus, the overall objective of this Phase I SBIR grant application is to determine which mTOT modulating agent has the potential to be the most effective in human ADPKD therapy. The agent with the best profile for limiting growth of cystic epithelial cells derived from ADPKD patients will be selected for further preclinical development. This future work will be the subject of a Phase II SBIR grant application. The overarching goal of this research effort is to develop a mTOT modulating insulin sensitizing agent for therapeutic intervention in a clinical trial of PKD patients.