Targeting the transcriptional co-activators YAP and TAZ with statins to prevent solid organ transplant rejection by HLA donor specific antibodies

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PROJECT ABSTRACT Solid organ transplant recipients exhibiting HLA donor specific antibodies (DSA) are at risk for graft loss due to chronic antibody-mediated rejection (cAMR) and develop a progressive vascular disease known as transplant vasculopathy (TV). Although cAMR and TV are highly significant clinical problems across different solid organ transplants the mechanisms by which DSAs directed against HLA I and HLA II contribute to cAMR and TV are not yet understood. Novel mechanistic targets and therapeutic approaches to prevent and treat cAMR and TV are urgently needed. Previously, we demonstrated that DSA-induced ligation of HLA molecules expressed in the surface of endothelial cells (ECs) induces signaling pathways that regulate survival, proliferation and migration, all of which are highly relevant to TV. However, the key transcriptional programs stimulated by ligation of HLA molecules remain to be identified. This gap in understanding hinders effective therapeutic targeting of DSA effector functions to prevent cAMR and TV. Based on our new results, we posit that the transcriptional co- activator Yes-Associated Protein (YAP) and its paralog WW-domain-containing Transcriptional co-Activator with PDZ-binding motif (TAZ), two central effectors of the Hippo pathway, are downstream points of convergence and integration in the mitogenic and migratory signaling initiated by DSAs in ECs. Although inhibition of the activity of transcription factors or their co-activators is a challenging strategy, recent evidence suggests a new avenue to target YAP/TAZ activity via drugs of the statin family. Importantly, epidemiological studies indicate that statins exert a beneficial effect in clinical transplant populations. Based on substantial preliminary studies, the central hypothesis of this proposal is that YAP and its paralog TAZ play a crucial role in promoting the proliferation and migration of ECs in response to DSAs and that the FDA-approved drugs of the statin family inhibit YAP/TAZ function in these cells. A fundamental translational implication of our hypothesis is that the drugs of the statin family can be an important element in preventing cAMR by blocking growth-promoting YAP/TAZ signaling in ECs. We propose to explore this central hypothesis by pursuing three Specific Aims: 1) Determine the regulation and function of YAP in human ECs stimulated with antibodies directed against HLA I or HLA II: role of Src kinases. 2) Define the mechanism(s) by which statins inhibit YAP function, proliferation and migration of ECs stimulated with antibodies directed against HLA I or HLA II. 3) Characterize the impact of statins on YAP and cAMR in vivo using a novel model of heart graft allograft that develop TV. We propose that the Src/YAP/TAZ axis plays a critical role in antibody-mediated EC proliferation and that statins inhibit EC proliferation and TV via YAP/TAZ inhibition. We anticipate that the Src/YAP/TAZ axis will emerge as a novel target in cAMR thus propelling further studies to reposition FDA-approved statins either singly or in combination with Src inhibitors for preventing chronic allograft injury induced by DSAs.