PROJECT SUMMARY The objective of this proposal is to develop antagonists of the bile acid receptor TGR5 as a potential treatment for polycystic liver disease (PLD), a genetic cholangiopathy characterized by hepatic cystogenesis. Cholangiopathies are a group of liver diseases in which cholangiocytes, the epithelial cells lining intrahepatic bile ducts, are the primary target. PLD, is incurable and exists as isolated Autosomal Dominant PLD or co-exists with Autosomal Dominant Polycystic Kidney Disease (ADPKD) and Autosomal Recessive PKD. Despite recent advances in the pathogenesis of PLD, there are no therapies for these devastating conditions. Our previous work implicated cAMP (increased in cystic cholangiocytes) as an important central component in the network of dysregulated signaling pathways in PLD and led us to cAMP-targeted strategies for disease treatment. We discovered TGR5, a G protein-coupled bile acid receptor (GPCR) linked to cAMP signaling, plays an important role in cAMP-driven hepatic cystogenesis in PLD. We demonstrated that TGR5 is overexpressed in cystic cholangiocytes in vitro and in vivo, and found TGR5 agonists increase intracellular cAMP, triggering cholangiocyte hyper-proliferation and enhancing cyst growth both in vitro and in PCK rats (worsening disease progression). Further findings support TGR5's role in the pathogenesis of hepatic cystogenesis. Thus, our objective is to develop antagonists to inhibit TGR5 activity, thus reducing hepatic cystogenesis in PLD. As no selective small molecule TGR5 antagonists have been reported, we completed an HTS identifying several promising leads including SBI-319. We propose this lead optimization campaign to develop orally available compounds for in vivo testing to validate TGR5 as a potential target for PLD. Central Hypothesis. Selective TGR5 antagonists will inhibit cAMP levels in cystic cholangiocytes, thus reducing cAMP-driven cell proliferation and hepatic cystogenesis, yielding a novel therapeutic target for PLD. To explore our central hypothesis, we will perform the following specific aims: Aim 1. To design and synthesize TGR5 antagonists orally active in vivo. Through iterative cycles of chemistry, we will identify compounds suitable for in vivo efficacy studies. Aim 2. To clarify the mechanisms of action of SBI-319 analogs in PLD. We will 1) assess SBI-319 analog effects on: (i) cAMP production in cystic cholangiocytes; (ii) cholangiocyte proliferation; and (iii) growth of hepatic cystic structures in 3D cultures; 2) examine the expression of TGR5 and G?s proteins, and their coupling upon treatment with SBI-319. Aim 3. To evaluate the efficacy of TGR5 antagonists as a treatment for PLD. We will assess effects of SBI-319 analogs on hepatic and renal cystogenesis and clarify the role of TGR5 inhibition in disease progression in vivo. In addition to PLD as a potential therapeutic application, findings show TGR5 is over-expressed in cholangiocarcinoma and is up-regulated in non-biliary cancers (breast, gastric, pancreas). Development of effective TGR5 antagonists would likely have therapeutic application beyond PLD.
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