Molecular mechanisms of cholesterol embolism

点击翻译按钮获取中文摘要

Cholesterol embolism syndrome (CES) is a complication of advanced atherosclerosis, where release of cholesterol crystals from atheromatous plaques, especially from the aorta, into the blood stream leading to peripheral embolism and tissue infarction. Frequently affected are the brain (stroke), eyes (blindness), gut (peritonitis), kidneys (akute kidney injury), and the lower extremities (blue toe syndrome). Despite CES is frequently lethal, little is known about the cellular and molecular pathogenesis as an animal model is not available. In our preliminary studies we have developed an animal model that is inducible in any gene-deficient or transgenic mouse strain. Important endpoints include infart size and glomerular filtration rate measured in awake and freely moving animals as an indicator of renal excretory function and a defining parameter of acute kidney injury. Based on promising preliminary data for the first time this project will systematically explore the cellular and molecular pathogenesis of CES. The following aspects will be studied in detail:1. The development of kidney infarcts and acute kidney injury depending from the amount and size of cholesterol crystals, the time course, the role of gender, time-of-day, diabetes, and hyperuricemia.2. The pathogenesis of intravascular crystal clot formation and options for revascularization.3. The molecular mechanisms of embolic kidney infarcts and the possibilities for therapeutic nephroprotection despite embolic vascular occlusions.This project will generate data for the first time providing insights into the cellular and molecular pathogenesis of this potentially lethal but poorly understood disease. It will also allow testing innovative therapeutic options in a new animal model.