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（由申请人提供）：抗磷脂抗体（APLA）与动脉和静脉血栓形成相关，是导致心血管疾病发病和死亡的主要原因。患有 APLA 相关血栓的个体需要终身抗凝治疗。磷脂，但 β2-糖蛋白 I (β2GPI)，一种丰富的磷脂结合糖蛋白，与血栓前状态相关。抗 β2GPI 抗体可能是由于其以 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 对 EC 的激活受到 Krüppel 样转录因子 (KLF)，特别是 KLF2 和 4 的调节。本申请的目标是确定 EC KLF 调节 APLA 的促血栓反应的机制。为了实现这一目标，我们将使用 KLF 表达的新型动物模型。在特定目标 1 中，我们将评估 APLA 诱导从缺乏 KLF2 和/或 KLF4 的小鼠中分离出的 EC 激活的能力，并确定 KLF2/4 如何影响内皮转录组。在具体目标 2 中，我们将结合这些研究来评估 KLF2/4 调节 APLA 介导的动脉、小动脉和静脉血栓形成的能力。确定他汀类药物阻断 APLA 介导的 EC 激活的能力是否依赖于 KLF。还将他汀类药物对 APLA 激活的 EC 转录组的影响与不存在他汀类药物时观察到的效果进行比较。 TLR4-NFκB 通路，并且我们已经证明 KLF2/4 阻断 APLA 激活 EC 的能力反映了 NFκB 共激活因子 CBP/p300 的隔离； NFκB 的其他转录共激活因子和共抑制因子的作用尚不清楚，在特定目标 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) 和共抑制因子。（NCoR/SMRT/HDAC）；我们还将确定他汀类药物是否以 KLF 依赖性方式抑制该复合物的组装，这些研究将提供有关调节的明确信息。 APLA 诱导 KLF 引起的 EC 激活和血栓形成，并提供有针对性的干预措施以防止 APS 破坏性后果的见解。