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:
- 金额:$ 24.89万
- 依托单位:
- 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:
- 关键词:ActinsAllograftingAntibodiesBindingBlood VesselsCell ProliferationCell TransplantationCellsCharacteristicsCholesterolChronicClinicalDevelopmentElementsEndothelial CellsExhibitsFDA approvedFamilyGenetic TranscriptionGraft RejectionGrowthGuidelinesHeart TransplantationHumanInjuryLesionLigationLipidsMediatingModelingMolecularOrgan TransplantationPI3K/AKTPTK2 genePathogenesisPathway interactionsPatientsPerivascular FibrosisPharmaceutical PreparationsPhosphorylationPlayPopulationPreventionProcessProteinsRegulationRiskRoleSignal PathwaySignal TransductionSolidSurfaceTranscription CoactivatorTransplantationVascular Diseasesantibody-mediated rejectionbasecell growthcell motilitycrosslinkdonor-specific antibodyepidemiology studyheart allograftin vivomigrationmouse modelnovelorgan transplant recipientparalogous genepreventprogramsprotein functionresponserhosrc-Family Kinasestargeted treatmenttherapeutic targettherapeutically effectivetranscription 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
表现出HLA供体特异性抗体(DSA)的实体器官移植受者处于移植物丢失的风险中,
慢性抗体介导的排斥反应(cAMR),并发展为进行性血管疾病,
移植血管病变(TV)。尽管cAMR和TV在不同的疾病中是非常重要的临床问题,
针对HLA I和HLA II的DSA促进cAMR的机制
电视还没有被理解。以前,我们证明DSA诱导的HLA分子连接
在内皮细胞表面表达的蛋白诱导信号通路,包括FAK/Src、PI 3 K/AKT、mTORC 1/2和
ERK调节生存、增殖和迁移,所有这些都与TV高度相关。但关键
由这些信号刺激的转录程序仍有待鉴定。根据新的初步结果,
我们证实转录辅激活因子Yes相关蛋白(雅普)及其旁的WW-domain-
含有具有PDZ结合基序(TAZ)的转录辅激活剂,两种Hippo的中枢效应物
信号通路是由DSA启动的信号级联中的下游汇聚点。虽然抑制
最近的证据表明,
通过他汀类降脂药物靶向雅普/TAZ活性的新途径。重要的是,
流行病学研究强烈表明他汀类药物在临床移植人群中发挥有益作用。
然而,分子机制仍然知之甚少。这种认识上的差距阻碍了有效的
DSA效应器功能的治疗靶向可预防cAMR和TV。这个问题的核心假设是
提示雅普及其周边TAZ在促进内皮细胞增殖和迁移中起着重要作用
以回应DSA。第二个假设是FDA批准的他汀类药物抑制雅普
在这些细胞中发挥作用。因此,他汀类药物可以是预防cAMR的重要因素,
阻断EC中促进生长的雅普/TAZ信号传导。我们将探讨这些假设,通过追求三个
具体目的:1)研究雅普在抗体刺激的人内皮细胞中的调节和功能
直接针对HLA I或HLA II:Src激酶的作用。2)定义他汀类药物抑制雅普的机制
用针对HLA I或HLA II的抗体刺激的EC的功能、增殖和迁移。第三章
使用一种新的心脏移植物同种异体移植物模型表征他汀类药物对体内雅普和cAMR的影响,
发展电视。我们预期雅普/TAZ轴在抗体介导的EC增殖中起关键作用
他汀类药物通过抑制雅普/TAZ抑制EC增殖和TV。如果实验结果证实
根据我们的假设,雅普/TAZ将成为开发新的有效药物的新靶点,
DSAs诱导的慢性同种异体移植物损伤。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Crosstalk between KRAS, SRC and YAP Signaling in Pancreatic Cancer: Interactions Leading to Aggressive Disease and Drug Resistance.
- DOI:10.3390/cancers13205126
- 发表时间:2021-10-13
- 期刊:
- 影响因子:5.2
- 作者:Rozengurt E;Eibl G
- 通讯作者:Eibl G
Obesity and Pancreatic Cancer: Insight into Mechanisms.
- DOI:10.3390/cancers13205067
- 发表时间:2021-10-10
- 期刊:
- 影响因子:5.2
- 作者:Eibl G;Rozengurt E
- 通讯作者:Rozengurt E
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{{ truncateString('ELAINE F REED', 18)}}的其他基金
Human Immunomics & Trained Immunity in Persistent Candidemia
人类免疫组学
- 批准号:
10551710 - 财政年份:2023
- 资助金额:
$ 24.89万 - 项目类别:
The role of HLA and its coreceptors in endothelial cell activation and leukocyte recruitment in antibody-mediated transplant rejection
HLA 及其辅助受体在抗体介导的移植排斥中内皮细胞激活和白细胞募集中的作用
- 批准号:
10231220 - 财政年份:2018
- 资助金额:
$ 24.89万 - 项目类别:
The role of HLA and its coreceptors in endothelial cell activation and leukocyte recruitment in antibody-mediated transplant rejection
HLA 及其辅助受体在抗体介导的移植排斥中内皮细胞激活和白细胞募集中的作用
- 批准号:
10462514 - 财政年份:2018
- 资助金额:
$ 24.89万 - 项目类别:
Mapping Immune Responses to CMV in Renal Transplant Recipients - Transplant Supplement
绘制肾移植受者对 CMV 的免疫反应 - Transplant Supplement
- 批准号:
10225673 - 财政年份:2017
- 资助金额:
$ 24.89万 - 项目类别:
Mapping Immune Responses to CMV in Renal Transplant Recipients
绘制肾移植受者对 CMV 的免疫反应
- 批准号:
10000838 - 财政年份:2017
- 资助金额:
$ 24.89万 - 项目类别:
Ischemia-Reperfusion Injury in Human Liver Transplantation: Reciprocal Regulation of Innate/Adaptive Immune Responses
人肝移植中的缺血再灌注损伤:先天/适应性免疫反应的相互调节
- 批准号:
9975701 - 财政年份:2017
- 资助金额:
$ 24.89万 - 项目类别:
Mapping Immune Responses to CMV in Renal Transplant Recipients
绘制肾移植受者对 CMV 的免疫反应
- 批准号:
10225355 - 财政年份:2017
- 资助金额:
$ 24.89万 - 项目类别:
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