Mixed Lineage Kinase 2 (MLK2) and vascular homeostasis

混合谱系激酶 2 (MLK2) 和血管稳态

基本信息

批准号：
10664335
负责人：
Shashi Kant
金额：
$ 17.31万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10664335
关键词：
ANGPTL2 gene ANGPTL4 gene Address Alleles Arteries Back Blood Vessels Blood flow Cardiovascular Diseases Cardiovascular system Cause of Death Cell physiology Cellular Stress Data Defect Development Elements Endothelial Cells Endothelium Exhibits Gene Expression Grant Hindlimb Homeostasis Hypoxia In Vitro Inflammation Ischemia Knock-out Knowledge Leukocyte Trafficking Link MAP Kinase Modules MAPK10 gene MAPK8 gene Malignant Neoplasms Mediating Metabolism Methods MicroRNAs Mitogen-Activated Protein Kinases Molecular Morbidity - disease rate Mus N-terminal Neoplasm Metastasis Neurodegenerative Disorders Pathway interactions Phenotype Phosphotransferases Physiological Play Proliferating Protein Kinase Recovery Role Signal Transduction Stress Testing Thrombosis Tissue Stains Tumor Angiogenesis Up-Regulation Vascular Diseases Vascular Endothelial Growth Factors Vascularization angiogenesis biological adaptation to stress blood vessel development cardiovascular health clinical development cost estimate disability endothelial dysfunction experimental study gain of function in vivo in vivo Model inhibitor loss of function member migration mouse model neural overexpression p38 Mitogen Activated Protein Kinase postnatal shear stress transcriptome sequencing

项目摘要

Project Summary Cardiovascular diseases are among the nation's leading causes of death and disability, with an estimated cost of more than $351 billion in the USA. Ischemia-induced angiogenesis plays an important role in the recovery of many vascular diseases. The endothelium plays an even more important role in vascular homeostasis as it regulates vascular tone, thrombosis, leukocyte trafficking, metabolism, and angiogenesis. Maintaining normal endothelial function requires balancing numerous physiological and pathophysiological stresses such as shear, hypoxia, and inflammation. Among the pathways mediating cellular stress, responses are the stress-activated members of the MAP kinase (MAPK) superfamily, which includes c-Jun N-terminal kinase (JNK) and p38 MAPK. JNK protein plays an important role in collateral artery formation during development. Recently, we have shown that neural JNK3 plays a significant role in blood flow recovery after hindlimb ischemia. In probing upstream components of the MAPK signaling cascade (MAP2K and MAP3K), we found that Mixed Lineage Kinase 2 (MLK2), a MAP3K and upstream regulator of MAPK, is expressed in endothelium and required for normal postnatal endothelial function. In fact, MLK2-deficient endothelial cells exhibit profound defects in angiogenesis as well as endothelial proliferation and migration. MLK2 also plays a significant role in VEGF signaling, which is required for proper endothelium function. RNA-seq data indicates that MLK2-deficient endothelial cells exhibit both basal and VEGF- induced upregulation of a broadly conserved microRNA, miR-146a, that has previously been linked to inflammation. Mimics of this miR-146a miRNA administered to wild-type endothelial cells recapitulate a broad spectrum of the MLK2-deficient phenotype, including defects in proliferation and VEGF signaling. Using these strategies, we should be able to develop a clear picture of how MLK2 influences endothelial function and vascular homeostasis. These data will be important as MLK inhibitors are being tested in the cancer field since very little data is understood regarding their cardiovascular consequences. Moreover, how Mlk2 influences the vasculature is a large gap in knowledge that we will address.

项目摘要心血管疾病是全国死亡和残疾的主要原因之一，估计成本美国超过3510亿美元。缺血诱导的血管生成在恢复中起重要作用许多血管疾病。内皮在血管稳态中起着更为重要的作用调节血管张力，血栓形成，白细胞运输，代谢和血管生成。保持正常内皮功能需要平衡许多生理和病理生理应力，例如剪切，缺氧和炎症。在介导细胞应激的途径中，反应是应力激活 MAP激酶（MAPK）超家族的成员，其中包括C-Jun N末端激酶（JNK）和P38 MAPK。 JNK蛋白在发育过程中在抵押动脉形成中起重要作用。最近，我们显示了该神经JNK3在后肢缺血后在血流恢复中起着重要作用。在探测上游 MAPK信号级联（MAP2K和MAP3K）的组件，我们发现混合谱系激酶2 （MLK2）是MAPK的MAP3K和上游调节剂，在内皮中表达，正常需要产后内皮功能。实际上，MLK2缺陷型内皮细胞在血管生成中表现出深刻的缺陷以及内皮增殖和迁移。 MLK2在VEGF信号传导中也起着重要作用，即适当的内皮功能所需。 RNA-seq数据表明MLK2缺陷型内皮细胞表现出基础和VEGF诱导的广泛保守的microRNA Mir-146a的上调，以前具有与炎症有关。对野生型内皮细胞施用的miR-146a miRNA的模仿概括了MLK2缺陷的表型，包括增殖和VEGF缺陷信号。使用这些策略，我们应该能够清楚地了解MLK2如何影响内皮功能和血管稳态。这些数据将很重要，因为正在测试MLK抑制剂在癌症领域，由于很少了解其心血管后果的数据。而且， MLK2如何影响脉管系统是我们将要解决的知识差距。