Einfluss von löslichem P-Selektin auf Hämostase und Thrombose

在内皮细胞、血小板和其他造血细胞表面表达的粘附受体在血栓形成和止血中起重要作用。这些受体中的一些在血浆中以可溶性形式可检测到，但它们的生理功能定义不清。可溶性P-选择素（sP-sel）最近被证明通过增强纤维蛋白的形成和在生长的血栓上的沉积而诱导。这种意想不到的功能导致了关于sP-sel在不同临床并发症中的积极作用的推测，其中已经检测到该分子的血浆水平增加。本研究旨在阐明sP-sel诱导的微粒形成的分子机制，研究这些微粒在血栓形成中的作用，并评估sP-sel在临床出血并发症中可能的有益作用。其中，方法学方法包括（1）用于研究小鼠血细胞的新型流式细胞术测定，（2）过度表达sP-sel的转基因小鼠的产生，（3）体外和离体流动室实验，以及关于血栓形成的体内活体显微镜研究，以及最后（4）人类出血并发症的临床相关小鼠模型。

Adhesion receptors expressed on the surface of endothelial cells, platelets, and other hematopoietic cells play an essential role in thrombosis and hemostasis. Some of these receptors are detectable in a soluble form in plasma, but their physiologic function(s) are poorly defined. Soluble P-selectin (sP-sel) was recently shown to induce by enhanced fibrin formation and deposition on growing thrombi. This unexpected function leads to speculations regarding an active role for sP-sel in different clinical complications where increased plasma levels of this molecule have been detected. The studies presented here aim to elucidate the molecular mechanisms involved in sP-sel-induced microparticel formation, to study the role of these microparticels in thrombus formation, and to evaluate possible beneficial effects of sP-sel in clinical bleeding complications. Among others, the methodological approaches include (1) novel flow cytometric assays for studies on mouse blood cells, (2) generation of transgenic mice overexpessing sP-sel, (3) in vitro and ex vivo flow chamber experiments, and in vivo intravital microscopic studies on thrombus formation, and finally (4) clinically relevant mouse models for human bleeding complications.