SNRK in ischemic vascular diseases

SNRK 在缺血性血管疾病中的作用

• 批准号: 10411882
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10411882
• 关键词: 5' -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

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 血管生成是响应于缺血和治疗的重要修复过程。 血管生成是治疗缺血性疾病最有希望的疗法。但 似乎递送单一生长因子或细胞类型不支持血管生成 足以防止缺血性损伤。因此，更好地了解生物学 血管生成对于鉴定治疗缺血性疾病的新靶点是必要的。我们 初步数据表明，蔗糖的mRNA和蛋白质水平显著增加， 非发酵1（Snf 1）相关激酶（SNRK），一种丝氨酸/苏氨酸激酶， AMP激活蛋白激酶（AMPK）相关的超家族，在心肌梗死患者中， 梗塞此外，SNRK的上调与新生血管形成水平的增加相关。 在人类缺血心肌中。同样，后肢缺血上调SNRK水平， 增加骨骼肌脉管系统中的新血管形成。最确凿的 SNRK在血管发生和血管生成中的重要作用的证据是， SNRK的杂合性缺失在生理和病理上均损害了新血管的形成， 病理条件和恶化的缺血性损伤的几种小鼠模型， 血管生成包括后肢缺血和左前降支冠状动脉（LAD） 心脏结扎因此，我们的中心假设是SNRK通过以下方式促进血管生成： 激活ITGB 1介导的EC迁移和细胞粘附。这一假设将得到检验 在动物模型和培养细胞中使用功能获得/丧失策略。目标1将 使用EC特异性snrk敲除，确定SNRK在调节血管生成中的作用 （snrkf/f/VE-cad-Cre+/−）小鼠和SNRK EC特异性转基因（snrk-TG）小鼠，并定义了SNRK EC特异性转基因小鼠的基因表达。 缺血/缺氧增加SNRK表达的机制。此外， SNRK在调节血管生成中的作用将通过功能的获得和丧失来确定。 方法在培养的主动脉环和EC。目的2是阐明 通过测试SNRK增加EC迁移，导致血管生成的假设，SNRK 通过激活ITGB 1介导的EC迁移和细胞粘附促进血管生成。的 成功完成拟议的研究将证明SNRK上调及其 β1整合素（ITGB 1）介导的EC迁移和粘附的相关激活是一种新的途径， 治疗缺血性血管疾病。由于新血管的形成也有助于 恶性，炎症，感染性和免疫性疾病，我们提出的研究可能有 缺血性血管疾病以外的影响。