Transcriptional control of endothelium in APS by Kruppel Like factors

Kruppel 样因子对 APS 中内皮细胞的转录控制

基本信息

批准号：
9307969
负责人：
MUKESH Kumar JAIN
金额：
$ 44.9万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-11 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9307969
关键词：
Address Affect Alpha Cell Animal Model Antibodies Anticoagulation Antigens Antiphospholipid Antibodies Arteries Binding Blood Vessels Cardiovascular system Caring Cells Clinical Complex Coupled Data E1A-associated p300 protein EP300 gene Endothelial Cells Endothelium Female Female of child bearing age GTP-Binding Protein alpha Subunits, Gs Gender Genetic Transcription Glycoproteins Goals Helium Immunoprecipitation In Vitro Individual Inflammatory Injury Intervention Kruppel-like transcription factors Laboratories Life Mediating Molecular Morbidity - disease rate Mus Nodal PCAF gene Partner in relationship Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phospholipids Proteins Publishing RNA Recurrence Regulation Risk Role TLR4 gene Testing Thrombosis Thrombus Transcription Coactivator Transcriptional Regulation Vascular Endothelial Cell Venous Venous Thrombosis arteriole beta 2-glycoprotein I genome-wide in vivo insight male mortality novel overexpression prevent public health relevance response transcriptome transcriptomics venule ward

项目摘要

DESCRIPTION (provided by applicant): Antiphospholipid antibodies (APLA) are associated with arterial and venous thrombosis, and are a cause of major cardiovascular morbidity and mortality. Individuals with APLA-associated thrombosis are treated with lifelong anticoagulation. The primary antigen for APLA is not phospholipid, but β2-glycoprotein I (β2GPI), an abundant phospholipid-binding glycoprotein. The prothrombotic state associated with anti-β2GPI antibodies may result from their ability to activate vascular endothelial cells (EC) in a β2GPI-dependent manner. We have demonstrated that activation of EC by APLA is regulated by Krüppel-like transcription factors (KLFs), particularly KLF2 and 4. The goal of this application i to define the mechanisms by which EC KLFs regulate the prothrombotic response to APLA. To accomplish this, we will use novel animal models in which the expression of KLFs has been altered in a global or cell-specific manner. In Specific Aim 1, we will assess the ability of APLA to induce activation of EC isolated from mice lacking KLF2 and/or KLF4, and determine how KLF2/4 affect the endothelial transcriptome in response to APLA. These studies will be coupled to assessment of the ability of KLF2/4 to modulate APLA-mediated arterial, arteriolar, and venular thrombosis in mice. In Specific Aim 2, we will determine whether the ability of statins to block APLA-mediated EC activation are KLF- dependent. The effects of statins on the transcriptome of APLA-activated EC will also be compared to that observed in the absence of statins. Finally, APLA activate EC through a TLR4-NFκB pathway, and we have demonstrated that the ability of KLF2/4 to block EC activation by APLA reflects sequestration of the NFκB coactivator CBP/p300; however, the role of other transcriptional co-activators and co-repressors of NFκB is unknown. In Specific Aim 3, we will assess the effects of APLA on assembly of the NFκB transcriptional complex, including co-activators (p300/PCAF) and co-repressors (NCoR/SMRT/HDACs); we will also determine whether statins inhibit assembly of this complex in a KLF-dependent manner. These studies will provide definitive information on the regulation of APLA-induced EC activation and thrombosis by KLFs, and provide insight into targeted interventions to prevent the devastating consequences of APS.

描述（由适用提供）：抗磷脂抗体（APLA）与动脉和静脉血栓形成有关，并且是主要心血管发病率和死亡率的原因。患有APLA相关血栓形成的个体通过终身抗凝治疗。 APLA的主要抗原不是磷脂，而是β2-糖蛋白I（β2GPI），一种丰富的磷脂结合糖蛋白。与抗β2GPI抗体相关的促血栓性状态可能是由于它们以β2GPI依赖性方式激活血管内皮细胞（EC）的能力。我们已经证明，APLA激活EC受Krüppel样转录因子（KLFS）的调节，尤其是KLF2和4。该应用I的目的是定义EC KLFS调节对APLA的实现抗体剂反应的机制。为此，我们将使用新型的动物模型，其中KLF的表达以全球或细胞特异性方式改变了。在特定目标1中，我们将评估APLA诱导从缺乏KLF2和/或KLF4的小鼠中孤立的EC激活的能力，并确定KLF2/4如何影响内皮转录组，以响应APLA。这些研究将与评估KLF2/4调节小鼠APLA介导的动脉，动脉和静脉血栓形成的能力。在特定的目标2中，我们将确定他汀类药物阻断APLA介导的EC激活的能力是否取决于KLF。他汀类药物对APLA激活EC的转录组的影响也将与不存在他汀类药物观察到的影响。最后，APLA通过TLR4-NFκB途径激活EC，我们已经证明了KLF2/4通过APLA阻断EC激活的能力反映了NFκB共激活器CBP/p300的隔离。但是，NFκB的其他转录共激活因子和共抑制剂的作用尚不清楚。在特定的目标3中，我们将评估APLA对NFκB转录复合物组装的影响，包括共激活因子（P300/PCAF）和共抑制器（NCOR/SMRT/HDACS）；我们还将确定他汀类药物是否以KLF依赖性方式抑制这种复合物的组装。这些研究将提供有关KLFS对APLA诱导的EC激活和血栓形成的调节的明确信息，并洞悉靶向干预措施，以防止AP的毁灭性后果。