SNRK in ischemic vascular diseases

SNRK 在缺血性血管疾病中的作用

基本信息

批准号：
9882513
负责人：
Zhonglin Xie
金额：
$ 74.45万
依托单位：
GEORGIA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9882513
关键词：
5&apos -AMP-activated protein kinase Address Adenoviruses Adhesions Animal Model Anterior Descending Coronary Artery Aorta Area Binding Binding Sites Biological Assay Biology Blood Vessels Brain Hypoxia-Ischemia Cardiac Cell Adhesion Cell Proliferation Cerebrovascular Disorders Clinical Clinical Trials Communicable Diseases Coronary heart disease Cultured Cells Data Dependovirus Development Disease Endothelial Cells Endothelium Green Fluorescent Proteins Growth Factor HIF1A gene Heart Human Hypoxia Immune System Diseases Impairment Infarction Inflammatory Integrins Ischemia KRP protein Knock-out Knowledge Left Ligation Malignant - descriptor Mediating Messenger RNA Molecular Mus Myocardial Infarction Myocardial Ischemia Pathologic Patients Peripheral arterial disease Phenotype Phosphotransferases Physiological Process Protein-Serine-Threonine Kinases Proteins Receptor Protein-Tyrosine Kinases Research Role Signal Pathway Signal Transduction Skeletal Muscle Small Interfering RNA Specificity Structure Sucrose Testing Tissues Transfection Transgenic Mice Transgenic Organisms Tube Up-Regulation Vascular Diseases angiogenesis cadherin 5 cell motility cell type disability effective therapy femoral artery hypoxia inducible factor 1 in vivo insight ischemic injury knock-down limb ischemia loss of function mRNA Expression member migration mortality mouse model neovascular novel overexpression prevent promoter protein expression repaired response therapeutic angiogenesis von Willebrand Factor

5&apos -AMP-activated protein kinase Address Adenoviruses Adhesions Animal Model Anterior Descending Coronary Artery Aorta Area Binding Binding Sites Biological Assay Biology Blood Vessels Brain Hypoxia-Ischemia Cardiac Cell Adhesion Cell Proliferation Cerebrovascular Disorders Clinical Clinical Trials Communicable Diseases Coronary heart disease Cultured Cells Data Dependovirus Development Disease Endothelial Cells Endothelium Green Fluorescent Proteins Growth Factor HIF1A gene Heart Human Hypoxia Immune System Diseases Impairment Infarction Inflammatory Integrins Ischemia KRP protein Knock-out Knowledge Left Ligation Malignant - descriptor Mediating Messenger RNA Molecular Mus Myocardial Infarction Myocardial Ischemia Pathologic Patients Peripheral arterial disease Phenotype Phosphotransferases Physiological Process Protein-Serine-Threonine Kinases Proteins Receptor Protein-Tyrosine Kinases Research Role Signal Pathway Signal Transduction Skeletal Muscle Small Interfering RNA Specificity Structure Sucrose Testing Tissues Transfection Transgenic Mice Transgenic Organisms Tube Up-Regulation Vascular Diseases angiogenesis cadherin 5 cell motility cell type disability effective therapy femoral artery hypoxia inducible factor 1 in vivo insight ischemic injury knock-down limb ischemia loss of function mRNA Expression member migration mortality mouse model neovascular novel overexpression prevent promoter protein expression repaired response therapeutic angiogenesis von Willebrand Factor

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项目摘要

Project Summary Angiogenesis is an important repair process in response to ischemia and therapeutic angiogenesis has been the most promising therapy for treating ischemic diseases. However, it appears that delivery of a single growth factor or cell type does not support angiogenesis sufficiently to prevent the ischemic damage. Thus, a better understanding of the biology of angiogenesis is necessary to identify new targets for treating ischemia diseases. Our preliminary data show that there are markedly increased mRNA and protein levels of sucrose non-fermenting 1 (Snf1)-related kinase (SNRK), a serine/threonine kinase, a novel member of the AMP-activated protein kinase (AMPK)-related superfamily, in the patients with myocardial infarction. Further, upregulated SNRK correlated with increased levels of neovascular formation in human ischemic myocardium. Similarly, hind limb ischemia upregulates SNRK levels and increased neovessel formation in the vasculature of skeletal muscles. The most conclusive evidence for the essential role of SNRK in vascular genesis and angiogenesis is that global heterozygous deletion of SNRK impaired new vessel formation in both physiological and pathological conditions and exacerbated ischemic injury in several murine models of angiogenesis including hind limb ischemia and left anterior descending coronary artery (LAD) ligation in hearts. Thus, our central hypothesis is that SNRK promotes angiogenesis by activating ITGB1-mediated EC migration and cell adhesion. This hypothesis will be tested using gain-/loss-of-function strategies in both animal models and cultured cells. Aim 1 will determine the role of SNRK in regulating angiogenesis, using EC-specific snrk knockout (snrkf/f/VE-cad-Cre+/−) mice and SNRK EC-specific transgenic (snrk-TG) mice and define the mechanism by which ischemia/hypoxia increases SNRK expression. In addition, the role of SNRK in regulating angiogenesis will be determined using gain- and loss-of-function approaches in cultured aortic rings and ECs. Aim 2 is to delineate the mechanism by which SNRK increases EC migration, leading to angiogenesis by testing the hypothesis that SNRK promotes angiogenesis by activating ITGB1-mediates EC migration and cell adhesion. The successful completion of the proposed study will demonstrate that SNRK upregulation and its related activation of β1 integrin (ITGB1)-mediated EC migration and adhesion is a new avenue to treat ischemic vascular diseases. Since the formation of new blood vessels also contributes to malignant, inflammatory, infectious and immune disorders, our proposed research may have implications beyond ischemic vascular disease.

项目摘要血管生成是响应缺血和治疗的重要修复过程血管生成一直是治疗缺血性疾病的最有希望的疗法。但是，它似乎单个生长因子或细胞类型的递送不支持血管生成足够防止缺血性损害。这是对生物学的更好理解血管生成是确定治疗缺血疾病的新靶标所需的。我们的初步数据表明，蔗糖的mRNA和蛋白质水平明显增加非发酵1（SNF1）相关激酶（SNRK），丝氨酸/苏氨酸激酶，新颖的成员 AMP激活的蛋白激酶（AMPK）相关的超家族，心肌患者梗塞。此外，更新的SNRK与新生血管形成水平的增加相关在人类缺血性心肌中。同样，后肢缺血上调了SNRK水平和在骨骼肌的脉管系统中增加了新壳的形成。最确定的 SNRK在血管生成和血管生成中的基本作用的证据是全球 SNRK的杂合缺失在生理和生理和病理状况和加剧的缺血性损伤血管生成包括后肢缺血和左前降冠状动脉（LAD）在心中结扎。这就是我们的中心假设是SNRK通过激活ITGB1介导的EC迁移和细胞粘合剂。该假设将进行检验在动物模型和培养的细胞中使用获得/功能丧失策略。目标1意志使用EC特异性SNRK敲除确定SNRK在确定血管生成中的作用（SNRKF/F/VE-CAD-CRE +/-）小鼠和SNRK EC特异性转基因（SNRK-TG）小鼠并定义缺血/缺氧增加SNRK表达的机制。另外，调节血管生成中的SNRK将使用功能丧失和功能丧失确定培养的主动脉环和EC中的方法。目的2是描述该机制 SNRK增加了EC的迁移，通过检验SNRK的假设导致了血管生成通过激活ITGB1 - 中的EC迁移和细胞粘合剂来促进血管生成。这拟议研究的成功完成将表明SNRK上调及其 β1整合素（ITGB1）介导的EC迁移和粘合剂的相关激活是新的途径治疗缺血性血管疾病。由于新血管的形成也有贡献对于恶性，炎症，传染性和免疫疾病，我们提出的研究可能已有缺血性血管疾病的含义。