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Cellular Reductive State Regulates Arteriogenesis

细胞还原状态调节动脉生成

基本信息

批准号：
10311084
负责人：
Christopher Bruce Pattillo
金额：
$ 36.5万
依托单位：
LOUISIANA STATE UNIV HSC SHREVEPORT
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10311084
关键词：
Acute Address Animals Antioxidants Arteries Attenuated Automobile Driving Binding Blood Vessels Blood flow Cardiovascular Diseases Cardiovascular Pathology Cell Culture Techniques Cell Proliferation Cell physiology Cells Chronic Clinical Cysteine Data Development Diabetes Mellitus Disease Progression Endothelial Cells Endothelium Environment Enzymes Equilibrium Frequencies Friction Functional disorder GCLC gene GCLM gene Genes Glutathione Glutathione Disulfide Homeostasis Hypertension In Vitro Incidence Inflammation Ischemia KDR gene Knock-out Ligation Mediating Modeling Molecular Mus Mutation Nitric Oxide Obesity Outcome Oxidative Stress Oxides Pathway interactions Perfusion Peripheral arterial disease Phosphorylation Physiological Play Post-Translational Protein Processing Production Protein Isoforms Proteins Reactive Oxygen Species Reperfusion Therapy Reporting Research Risk Factors Role Severity of illness Signal Transduction Smooth Muscle Myocytes Testing Therapeutic Therapeutic Intervention Time Tissues Vascular Diseases Vascular remodeling Vasodilation antioxidant therapy blood vessel occlusion clinically relevant glutathione peroxidase improved in vivo insight monocyte mouse model mutant novel oxidant stress oxidation receptor recruit response shear stress src-Family Kinases therapy development tool

项目摘要

PROJECT ABSTRACT The incidence of tissue ischemia resulting from progressive vascular occlusion is on the rise, and leads to several cardiovascular pathologies characterized by arterial blockage such as peripheral artery disease. Revascularization of tissue is time sensitive and essential to restore adequate blood flow. Decreases in antioxidant capacity such as decreases in the reduced form of glutathione (GSH) concentrations and corresponding increases in oxidant stress are hallmarks of disease progression and endothelial cell dysfunction. Decreases in glutathione are thought to correspond with a linear increase in disease severity that is a poorly understood relationship. The current proposal seeks to: (a) determine the influence of changing GSH:GSSG levels on protein glutathionylation driving vascular endothelial growth factor receptor 2 (VEGFR2) signaling in arteriogenesis, (b) determine the role of glutathionylation in oxidative and shear stress induced endothelial cell NF-κB signaling, (c) study in vivo arteriogenesis in murine models that have mutations in the GSH synthesis pathway, and are undergoing ligations to mimic acute and chronic peripheral artery disease, and (d) restore defective arteriogenesis progression by stimulating a more reductive cellular environment to improve endothelial cell function. We will test the central hypothesis that a critical balance between the reductive and oxidative cellular environments drives optimal VEGFR2 signaling to mediate arteriogenic remodeling in response to increased shear and oxidant stress. The proposed aims will utilize in vitro cultures of endothelial cells isolated from our glutathione synthesis mutant murine animals to generate data focusing on glutathionylation of proteins driving VEGFR2 specific signaling. The proposed aims also include our in vivo mouse models of arterial blockage as clinically relevant models of vascular remodeling. Specific Aim 1 will focus on determining the role of glutathionylation in VEGFR2 activation during endothelial cell arteriogenic signaling. Specific Aim 2 will assess the role of low level oxidant stress and its control over glutathionylation driving arteriogenic signaling. We will utilize in vitro cultures of endothelial cells isolated from our glutathione synthesis mutant murine animals to study signaling in aims 1 and 2. Specific Aim 3 will assess the role of the oxidative/reductive balance in arteriogenesis remodeling in vivo. Here we will use our in vivo mouse models of arterial blockage. Successful completion of this project will provide new insights into the mechanism by which glutathione regulates arteriogenesis in a physiologic range of GSH:GSSG following arterial ligation. Such information could be the basis for new intervention therapies developed to precisely control arteriogenesis following artery blockage. Enhancing the vascular remodeling potential of tissue through manipulation of glutathione and protein glutathionylation may represent a critical first step in attenuating tissue damage due to vascular occlusion.

项目摘要