Mixed Lineage Kinase 2 (MLK2) and vascular homeostasis

混合谱系激酶 2 (MLK​​2) 和血管稳态

• 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
• 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

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 心血管疾病是美国死亡和残疾的主要原因之一， 在美国超过3510亿美元。缺血诱导的血管生成在缺血性脑血管病的恢复中起着重要作用。 许多血管疾病。内皮细胞在血管稳态中起着更重要的作用， 调节血管张力、血栓形成、白细胞运输、代谢和血管生成。维持正常 内皮功能需要平衡许多生理和病理生理应力如剪切， 缺氧和炎症。在介导细胞应激的途径中，反应是应激激活的 MAP激酶（MAPK）超家族的成员，其包括c-Jun N-末端激酶（JNK）和p38 MAPK。 JNK蛋白在发育过程中侧支动脉的形成中起重要作用。最近，我们发现 神经JNK 3在后肢缺血后血流恢复中起重要作用。在上游探测中 通过对MAPK信号级联反应的两个重要组成部分（MAP 2K和MAP 3 K）的研究，我们发现混合谱系激酶2（MLK 2）在MAPK信号级联反应中起重要作用。 （MLK 2）是一种MAP 3 K和MAPK上游调节因子，在内皮细胞中表达，是正常生长所需的 出生后内皮功能。事实上，MLK 2缺陷型内皮细胞在血管生成方面表现出严重缺陷 以及内皮细胞增殖和迁移。MLK 2还在VEGF信号传导中起重要作用， 维持正常的内皮功能。RNA-seq数据表明MLK 2缺陷型内皮细胞表现出 基础和VEGF诱导的广泛保守的microRNA，miR-146 a的上调， 与炎症有关。给予野生型内皮细胞的miR-146 a miRNA模拟物 概括了MLK 2缺陷表型的广泛范围，包括增殖和VEGF缺陷， 发信号。使用这些策略，我们应该能够清楚地了解MLK 2如何影响 内皮功能和血管稳态。这些数据将是重要的MLK抑制剂正在测试 在癌症领域，因为很少有关于其心血管后果的数据。此外，委员会认为， Mlk 2如何影响脉管系统是我们将要解决的知识上的一个巨大空白。