Magnetic nanoparticles assisted modulation of the vascular cGMP system

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In the first funding period, we focused on the use of magnetic nanoparticles (MNPs) to enhance and target lentiviral (LV) gene transfer in the vascular system. A broad spectrum of MNPs was studied to optimize LV gene transfer in vitro and ex vivo. In addition, first studies in vivo were performed. Based on this work, we will now focus on the study of the nitric oxide (NO)/cGMP pathway, which is essential for vascular homeostasis. In the present proposal, we will study novel mechanisms that control NO and cGMP production. The major focus will be on cGMP-dependent protein kinase (protein kinase G, PKG) and its downstream targets that mediate the NO/cGMP/PKG effects. We have preliminary data suggesting that a so far unknown pathway involving a PKG substrate and the small GTPase Rac regulate cellular cGMP concentrations. Moreover, we will study the link between cGMP/PKG signaling and NO production in the endothelium. Without the application of MNPs and magnetic gradient field an efficient and targeted transduction of vessels under flow conditions is not possible. Therefore, we will use optimized LV/MNP complexes to study the physiological effects of the signaling pathways in the vascular system. Apart from ex vivo perfusion systems that also allow for force measurements as an important physiological read-out, we will further develop the LV/MNP system using MNP-containing microbubbles (MBs) with the aim to achieve efficient gene transfer to vessels in the vascular system in vivo.