Molecular mechanisms of cholesterol embolism

胆固醇栓塞综合征（CES）是晚期动脉粥样硬化的一种并发症，即胆固醇晶体从动脉粥样硬化斑块（尤其是主动脉）释放到血液中，导致外周栓塞和组织梗死。经常受影响的是大脑（中风）、眼睛（失明）、肠道（腹膜炎）、肾脏（急性肾损伤）和下肢（蓝趾综合征）。尽管CES通常是致命的，但由于没有动物模型，对其细胞和分子发病机制知之甚少。在我们的初步研究中，我们已经开发了一种动物模型，可以在任何基因缺陷或转基因小鼠株中诱导。重要的终点包括在清醒和自由活动的动物中测量的梗死大小和肾小球滤过率，作为肾脏排泄功能的指标和急性肾损伤的定义参数。本项目将首次以有希望的初步数据为基础，系统探索CES的细胞和分子发病机制。本文将从以下几个方面进行详细的研究：肾梗死和急性肾损伤的发生取决于胆固醇结晶的数量和大小、时间进程、性别、时间、糖尿病和高尿酸血症的作用。血管内结块形成的发病机制及血运重建的选择。栓塞性肾梗死的分子机制和栓塞性血管闭塞后治疗性肾保护的可能性。该项目将首次产生数据，为这种潜在致命但知之甚少的疾病的细胞和分子发病机制提供见解。它还将允许在一种新的动物模型中测试创新的治疗方案。

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.