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

• 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
• 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; 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

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.

抽象的 表现出HLA供体特异性抗体（DSA）的固体器官移植受者有可能发生移植的风险 慢性抗体介导的排斥反应（CAMR），并形成一种进行性血管疾病 移植血管病（电视）。尽管CAMR和电视是不同不同的临床问题 实体器官移植DSA针对HLA I和HLA II的机制有助于CAMR 电视尚未理解。以前，我们证明了DSA诱导的HLA分子的连接 在EC表面表达的诱导信号通路，包括FAK/SRC，PI3K/AKT，MTORC1/2和 调节生存，增殖和迁移的ERK，所有这些都与电视高度相关。但是，关键 这些信号刺激的转录程序仍有待确定。基于新的初步结果 我们认为转录共激活因子相关蛋白（YAP）及其旁系同源物WW-Domain- 包含具有PDZ结合基序（TAZ）的转录共激活器，这是河马的两个核心效应子 途径是DSA引发的信号级联反向的下游点。虽然抑制 最近的证据表明，转录因素或其共激活因子的活动是一种具有挑战性的策略 通过他汀类药物的降脂药物靶向YAP/TAZ活动的新途径。重要的是， 流行病学研究强烈表明他汀类药物对临床移植人群产生有益的作用。 但是，分子机制仍然很少理解。理解阻碍有效的差距 DSA效应功能的治疗靶向以防止CAMR和TV。中心假设 提议是Yap及其旁系同源物TAZ在促进EC的扩散和迁移中起着至关重要的作用 响应DSA。第二个假设是他汀类药物的FDA批准药物抑制了YAP 在这些细胞中功能。因此，他汀类药物的药物可能是防止CAMR通过的重要因素 阻止EC中促进生长的YAP/TAZ信号传导。我们将通过追求三个来探讨这些假设 具体目的：1）确定用抗体刺激的人类EC中YAP的调节和功能 针对HLA I或HLA II：SRC激酶的作用。 2）定义他汀类药物抑制YAP的机制 针对HLA I或HLA II的抗体刺激的EC的功能，增殖和迁移。 3） 使用一种新型的心脏移植同种异体移植模型来表征他汀类药物对YAP和CAMR在体内的影响 开发电视。我们预计YAP/TAZ轴在抗体介导的EC增殖中起着至关重要的作用 他汀类药物通过YAP/TAZ抑制抑制EC的增殖和TV。如果实验结果证实 我们的假设，YAP/TAZ将成为开发用于防止新的和有效药物的新目标 DSA诱导的慢性同种异体移植损伤。