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Browsing by Subject "Bifunctional protein"

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    Entwicklung und Charakterisierung des rekombinanten, bifunktionalen Proteins SDF1-GPVI und dessen Einfluss auf die myokardialen Reparaturmechanismen
    (2012) Ziegler, Melanie; Graeve, Lutz
    Cardiovascular diseases like myocardial infarction, arteriosclerosis and coronary heart disease are the leading cause of death worldwide. Because of this, development of novel and innovative biopharmaceutical approaches is very important to improve the therapy of cardiovascular diseases. Especially after myocardial infarction, promoting cardiac repair mechanisms is of vital importance to preserve cardiac function and decrease scar size. The chemokine ?stromal cell-dervied factor-1? (SDF-1) plays a crucial role in stem cell homing and is upregulated after myocardial infarction. It is already known that the SDF-1/ CXCR4 axis promotes myocardial repair. In this study we connected SDF-1 with an anchor structure to accumulate this chemokine specifically at the infarcted myocardium. The anchor structure consists of the soluble glycoprotein VI (GPVI). GPVI is the major collagen receptor on platelets and binds to nearly all collagen types and other proteins of the extracellular matrix like fibronectin and vitronectin. Hence, SDF1-GPVI specifically accumulates at the injured tissue and attracts progenitor cells from the blood stream to the lesion site. During the course of this study, the recominant, bifunctional protein SDF1-GPVI, consisting of human SDF-1 and soluble human GPVI, was generated. Subsequently, the functional efficacy of the SDF-1 and GPVI domains were proven by several functional assays and the bifunctionality of SDF1-GPVI was determined by dynamic adhesion in a flow chamber system. Further, in vitro studies showed that SDF1-GPVI triggers chemotaxis of haematopoetic progenitor cells (HPCs), enhances and accelerates endothelial differentiation of HPCs and preserves survival of HPCs. Furthermore, using the ?Chorioallantoic Membrane? (CAM) assay SDF1-GPVI revealed proangiogenic effects in ovo. Prior to in vivo analysis, a pharmacokinetic study showed that SDF1-GPVI has a biological half-life >48 h. After induction of myocardial infarction, treatment with SDF1-GPVI and G-CSF lead to a significantly decrease in infarct size and to a significantly preserved myocardial function 28 days after transient ischemia/reperfusion. Additional positive effects were enhanced homing of GFP-labelled ?bone marrow cells? (BMCs), increased recruitment of CXCR4-positive cells and enhanced neovascularisation in the infarcted myocardium. Therefore, the bifunctional protein SDF1-GPVI bears the potential to serve as a promising biopharmaceutical therapeutic to promote myocardial repair especially after myocardial infarction.