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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.

项目总结