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.

项目总结