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Ischemia/Reperfusion injury and Myocardial edema

缺血/再灌注损伤和心肌水肿

基本信息

批准号：
10718260
负责人：
Michael Simons
金额：
$ 61.03万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10718260
关键词：
Acute Acute myocardial infarction Adherence Affect Affinity Angiogenesis Inhibitors Animal Model Arrhythmia BAY 54-9085 Binding Biological Blocking Antibodies Blood flow Brain Cardiac Output Cardiovascular Pathology Chronic Chronic Phase Coronary Data Defect Development Edema Electrophysiology (science)Endothelial Cells Endothelium Epidemic Event Extracellular Matrix Fibrosis Genetically Engineered Mouse Goals Hand Heart Heart Injuries Heart failure Hemorrhage Human Hypokalemia Immunoglobulin G Incidence Infarction Inflammation Inflammatory Injury Ischemia KDR gene Kinetics Knock-out Lead Left Ventricular Dysfunction Link Liquid substance Lymphatic function Maintenance Malignant Neoplasms Membrane Molecular Monoclonal Antibodies Mus Myocardial Myocardial Infarction Myocardial Ischemia Myocardial Reperfusion Injury Myocardial dysfunction Organ Outcome Pathogenesis Permeability Pharmaceutical Preparations Phenotype Phosphoric Monoester Hydrolases Phosphorylation Production Protein Dephosphorylation Public Health Recovery of Function Reperfusion Injury Reperfusion Therapy Role Safety Severities Signal Transduction Site Structure Therapeutic Time Translating Translations Validation Vascular Endothelial Growth Factors Vascular Permeabilities Ventricular Arrhythmia Ventricular Tachycardia acute stroke bevacizumab blocking factor cadherin 5 fibroglycan heart function human monoclonal antibodies improved in vivo interstitial microCT mutant myocardial infarct sizing novel novel strategies pre-clinical preservation prevent receptor response sudden cardiac death systemic inflammatory response vascular endothelium permeability wound healing wound injury

项目摘要

Project Summary Uncontrolled inflammation is a key driver of acute and chronic cardiovascular pathology. However, the accompanying edema, one of the four cardinal signs of inflammation defined by Celsus and Galen two millennia ago, is poorly understood and often ignored at the mechanistic level. Yet ample evidence shows its causal roles in ischemia reperfusion injury (IRI) and resultant sequelae in the heart, brain, and other organs. While a number of molecules can induce edema formation, vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF) has been viewed as the key component of IRI-associated edema development. There are a number of drugs capable of blocking VEGF signaling, including vascular permeability that are widely used as anti- angiogenic cancer and ophthalmologic drugs such as bevacizumab, sorafenib, sunitinib and pazopanib among others. However, none of them can be used in acute/chronic ischemia settings due to the induced loss of blood vasculature. Exciting new data from our lab have demonstrated that it is possible to selectively block VEGF- induced permeability defects without affecting other aspects of its signaling, thereby eliminating anti-angiogenic effects of non-selective anti-VEGF therapies. In preliminary studies, blocking VEGF-blocking edema formation leads to a ~50% reduction in the size of myocardial infarction and preservation of LV systolic and diastolic function and suppression of VT inducibility. With these preliminary results in hand, we propose to examine the functional effects myocardial edema and evaluate the effect of anti-edema therapies in this setting.

项目总结