SNRK in ischemic vascular diseases

SNRK 在缺血性血管疾病中的作用

• 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
• 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' -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.

项目概要 血管生成是响应缺血和治疗的重要修复过程 血管生成已成为治疗缺血性疾病最有前途的疗法。然而，它 似乎单一生长因子或细胞类型的递送不支持血管生成 足以预防缺血性损伤。因此，可以更好地了解 血管生成对于确定治疗缺血性疾病的新靶点是必要的。我们的 初步数据表明，蔗糖的 mRNA 和蛋白质水平显着增加 非发酵 1 (Snf1) 相关激酶 (SNRK)，一种丝氨酸/苏氨酸激酶，是 心肌病患者中的 AMP 激活蛋白激酶 (AMPK) 相关超家族 梗塞。此外，SNRK 上调与新血管形成水平增加相关 在人类缺血性心肌中。 Similarly, hind limb ischemia upregulates SNRK levels and 骨骼肌脉管系统中新血管的形成增加。最有定论的 SNRK 在血管发生和血管生成中发挥重要作用的证据是全球性的 SNRK 的杂合缺失损害了生理和心理上新血管的形成 几种小鼠模型的病理状况和加剧的缺血性损伤 血管生成，包括后肢缺血和左冠状动脉前降支 (LAD) 结扎在心中。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 ITGB1 介导的 EC 迁移和细胞粘附。这个假设将被检验 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 缺血/缺氧增加 SNRK 表达的机制。此外，作用 SNRK 在调节血管生成中的作用将通过功能获得和丧失来确定 培养主动脉环和 EC 的方法。目标 2 是描述机制 SNRK 增加 EC 迁移，通过检验 SNRK 的假设导致血管生成 通过激活 ITGB1 介导 EC 迁移和细胞粘附来促进血管生成。这 拟议研究的成功完成将证明 SNRK 上调及其 β1整合素（ITGB1）介导的EC迁移和粘附的相关激活是一条新途径 治疗缺血性血管疾病。由于新血管的形成也有助于 对于恶性、炎症、传染性和免疫性疾病，我们提出的研究可能有 其影响超出了缺血性血管疾病的范围。