CKD shows progressive kidney fibrosis (TIF). SNPs in Shroom3 (~40% prevalence) increase CKD-risk but poor understanding has hindered therapeutics, and those at risk continue to progress. Our lab studies the role of Shroom3 in TIF/CKD. We showed that more Shroom3 in kidney cells sets up a “fibro-inflammatory” mileu for progression. Using new mouse models of TIF, we saw that Rho-kinase (Rock)-binding by Shroom3 is critical for these effects. We developed small-molecule inhibitors of Shroom3-Rock interaction (P2Is), and showed that P2Is inhibited TIF in vivo. In Aim-1 ($150 K), we will optimize P2Is for potent kidney cell targeting of Shroom3-Rock interaction, and extensively test these agents for efficacy invivo. In Aim-2 ($150K), to hasten translation to humans, we will test our lead P2Is in a unique ex-vivo TIF model in kidney organoids developed from either wild-type- or Shroom3-SNP carrying individuals to develop a generalizable strategy for individuals at risk for progressive CKD.