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Targeting YAP with statins to prevent antibody-mediated transplant rejection

用他汀类药物靶向 YAP 预防抗体介导的移植排斥

基本信息

批准号：
10320048
负责人：
ELAINE F REED
金额：
$ 24.89万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-18 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10320048
关键词：
Actins Allografting Antibodies Binding Blood Vessels Cell Proliferation Cell Transplantation Cells Characteristics Cholesterol Chronic Clinical Development Elements Endothelial Cells Exhibits FDA approved Family Genetic Transcription Graft Rejection Growth Guidelines Heart Transplantation Human Injury Lesion Ligation Lipids Mediating Modeling Molecular Organ Transplantation PI3K/AKT PTK2 gene Pathogenesis Pathway interactions Patients Perivascular Fibrosis Pharmaceutical Preparations Phosphorylation Play Population Prevention Process Proteins Regulation Risk Role Signal Pathway Signal Transduction Solid Surface Transcription Coactivator Transplantation Vascular Diseases antibody-mediated rejection base cell growth cell motility crosslink donor-specific antibody epidemiology study heart allograft in vivo migration mouse model novel organ transplant recipient paralogous gene prevent programs protein function response rho src-Family Kinases targeted treatment therapeutic target therapeutically effective transcription factor

项目摘要

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. Previously, we demonstrated that DSA-induced ligation of HLA molecules expressed in the surface of ECs induces signaling pathways, including FAK/Src, PI3K/AKT, mTORC1/2 and ERK that regulate survival, proliferation and migration, all of which are highly relevant to TV. However, the key transcriptional programs stimulated by these signals remain to be identified. Based on new preliminary 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 in the signaling cascade initiated by DSAs. 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 lipid-lowering drugs of the statin family. Importantly, epidemiological studies strongly indicate that statins exert a beneficial effect in clinical transplant populations. However, the molecular mechanism remain poorly understood. This gap in understanding hinders effective therapeutic targeting of DSA effector functions to prevent cAMR and TV. 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. A second hypothesis is that the FDA-approved drugs of the statin family inhibit YAP function in these cells. Thus, drugs of the statin family can be an important element in preventing cAMR via blocking growth-promoting YAP/TAZ signaling in ECs. We will explore these hypotheses 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 anticipate that the YAP/TAZ axis plays a critical role in antibody-mediated EC proliferation and that statins inhibit EC proliferation and TV via YAP/TAZ inhibition. If the experimental results substantiate our hypotheses, YAP/TAZ will emerge as novel targets for developing new and potent drugs for preventing chronic allograft injury induced by DSAs.

摘要