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

用他汀类药物靶向转录共激活剂 YAP 和 TAZ，以防止 HLA 供体特异性抗体导致实体器官移植排斥

• 批准号: 10734277
• 负责人: Robert L Fairchild
• 金额: $ 72.34万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-19 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734277
• 关键词: Actins; Allografting; Antibodies; Blood Vessels; Cell Proliferation; Cell Transplantation; Cells; Characteristics; Chronic; Clinical; Clinical Trials; Dasatinib; Development; Drug usage; Elements; Endothelial Cells; Evolution; Exhibits; FDA approved; Family; Funding; Genetic Transcription; Grant; Growth; Heart Transplantation; Human; Injury; Lesion; Ligation; Mediating; Modeling; Molecular; Oncology; Organ; Organ Transplantation; PI3K/AKT; PTK2 gene; Pathogenesis; Pathway interactions; Perivascular Fibrosis; Pharmaceutical Preparations; Phosphorylation; Play; Population; Positioning Attribute; Prevention; Process; Proliferating; Proteins; Regulation; Risk; Role; Serine; Signal Induction; Signal Pathway; Signal Transduction; Solid; Surface; Testing; Therapeutic; Transcription Coactivator; Transcriptional Coactivator with PDZ-Binding Motif; Transplantation; Tyrosine; Tyrosine Phosphorylation; Vascular Diseases; antibody-mediated rejection; cell growth; cell motility; crosslink; donor-specific antibody; epidemiology study; heart allograft; in vivo; inhibitor; migration; novel; organ transplant recipient; organ transplant rejection; paralogous gene; prevent; programs; protein function; response; rho; src-Family Kinases; therapeutic target; therapeutically effective; transcription factor

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.

项目摘要 表现出 HLA 供体特异性抗体 (DSA) 的实体器官移植受者由于以下因素而面临移植物丢失的风险： 慢性抗体介导的排斥反应 (cAMR) 并发展为一种称为移植的进行性血管疾病 血管病变（电视）。尽管 cAMR 和 TV 是跨不同实体器官的非常重要的临床问题 移植针对 HLA I 和 HLA II 的 DSA 促进 cAMR 和 TV 的机制 还没明白。预防和治疗 cAMR 和 TV 的新机制靶点和治疗方法 是迫切需要的。之前，我们证明了 DSA 诱导的 HLA 分子的连接 内皮细胞（EC）表面诱导调节生存、增殖和迁移的信号通路， 所有这些都与电视高度相关。然而，HLA 连接刺激的关键转录程序 分子仍有待鉴定。这种理解上的差距阻碍了 DSA 的有效治疗靶向 效应器功能可防止 cAMR 和 TV。根据我们的新结果，我们认为转录共 激活剂 Yes 相关蛋白 (YAP) 及其旁系同源 WW 结构域包含转录辅激活剂 PDZ 结合基序 (TAZ) 是 Hippo 通路的两个中心效应子，是下游的汇聚点 以及 EC 中 DSA 启动的有丝分裂和迁移信号的整合。虽然抑制 转录因子或其共激活子的活性是一种具有挑战性的策略，最近的证据表明一种新的方法 通过他汀类药物靶向 YAP/TAZ 活性的途径。重要的是，流行病学研究表明 他汀类药物对临床移植人群发挥有益作用。基于大量的初步研究， 该提案的中心假设是 YAP 及其旁系同源 TAZ 在促进 ECs 响应 DSA 的增殖和迁移以及 FDA 批准的他汀类药物 抑制这些细胞中的 YAP/TAZ 功能。我们的假设的一个基本转化意义是药物 他汀类药物家族的成员可以通过阻断促进生长的 YAP/TAZ 来预防 cAMR EC 中的信号传导。我们建议通过追求三个具体目标来探索这一中心假设：1）确定 使用针对 HLA I 或 HLA II 的抗体刺激的人 EC 中 YAP 的调节和功能： Src 激酶的作用。 2) 明确他汀类药物抑制YAP功能、增殖和迁移的机制 用针对 HLA I 或 HLA II 的抗体刺激的 ECs。 3) 描述他汀类药物对 YAP 的影响 和 cAMR 体内使用开发 TV 的新型心脏移植同种异体移植模型。我们建议 Src/YAP/TAZ 轴在抗体介导的 EC 增殖中发挥着关键作用，他汀类药物通过抑制 EC 增殖和 TV YAP/TAZ 抑制。我们预计 Src/YAP/TAZ 轴将成为 cAMR 的新靶标 推动进一步研究重新定位 FDA 批准的他汀类药物，无论是单独使用还是与 Src 抑制剂联合使用 用于预防 DSA 引起的慢性同种异体移植损伤。