TY - JOUR A1 - Tilstam, Pathricia V. A1 - Gijbels, Marion J. A1 - Habbeddine, Mohamed A1 - Cudejko, Celine A1 - Asare, Yaw A1 - Theelen, Wendy A1 - Zhou, Baixue A1 - Döring, Yvonne A1 - Drechsler, Maik A1 - Pawig, Lukas A1 - Simsekyilmaz, Sakine A1 - Koenen, Rory R. A1 - de Winther, Menno P. J. A1 - Lawrence, Toby A1 - Bernhagen, Jürgen A1 - Zernecke, Alma A1 - Weber, Christian A1 - Noels, Heidi T1 - Bone Marrow-Specific Knock-In of a Non-Activatable Ikkα Kinase Mutant Influences Haematopoiesis but Not Atherosclerosis in Apoe-Deficient Mice JF - PLOS ONE N2 - Background: The Ikkα kinase, a subunit of the NF-kappa B-activating IKK complex, has emerged as an important regulator of inflammatory gene expression. However, the role of Ikkα-mediated phosphorylation in haematopoiesis and atherogenesis remains unexplored. In this study, we investigated the effect of a bone marrow (BM)-specific activation-resistant Ikk alpha mutant knock-in on haematopoiesis and atherosclerosis in mice. Methods and Results: Apolipoprotein E (Apoe)-deficient mice were transplanted with BM carrying an activation-resistant Ikkα gene (Ikkα(AA/AA) Apoe(-/-)) or with Ikkα(+/+) Apoe(-/-) BM as control and were fed a high-cholesterol diet for 8 or 13 weeks. Interestingly, haematopoietic profiling by flow cytometry revealed a significant decrease in B-cells, regulatory T-cells and effector memory T-cells in Ikkα(AA/AA) Apoe(-/-) BM-chimeras, whereas the naive T-cell population was increased. Surprisingly, no differences were observed in the size, stage or cellular composition of atherosclerotic lesions in the aorta and aortic root of Ikkα(AA/AA) Apoe(-/-) vs Ikkα(+/+) Apoe(-/-) BM-transplanted mice, as shown by histological and immunofluorescent stainings. Necrotic core sizes, apoptosis, and intracellular lipid deposits in aortic root lesions were unaltered. In vitro, BM-derived macrophages from Ikkα(AA/AA) Apoe(-/-) vs Ikkα(+/+) Apoe(-/-) mice did not show significant differences in the uptake of oxidized low-density lipoproteins (oxLDL), and, with the exception of Il-12, the secretion of inflammatory proteins in conditions of Tnf-α or oxLDL stimulation was not significantly altered. Furthermore, serum levels of inflammatory proteins as measured with a cytokine bead array were comparable. Conclusion: Our data reveal an important and previously unrecognized role of haematopoietic Ikkα kinase activation in the homeostasis of B-cells and regulatory T-cells. However, transplantation of Ikkα AA mutant BM did not affect atherosclerosis in Apoe(-/-) mice. This suggests that the diverse functions of Ikkα in haematopoietic cells may counterbalance each other or may not be strong enough to influence atherogenesis, and reveals that targeting haematopoietic Ikkα kinase activity alone does not represent a therapeutic approach. KW - NF-KAPPA-B KW - regulatory T cells KW - indoleamine 2,3-dioxygenase KW - dendritic cells KW - gene expression KW - increases atherosclersosis KW - receptor KW - inhibition KW - pathway KW - beta Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117450 VL - 9 IS - 2 ER - TY - JOUR A1 - Projahn, Delia A1 - Simsekyilmaz, Sakine A1 - Singh, Smriti A1 - Kanzler, Isabella A1 - Kramp, Birgit K. A1 - Langer, Marcella A1 - Burlacu, Alexandrina A1 - Bernhagen, Jürgen A1 - Klee, Doris A1 - Zernecke, Alma A1 - Hackeng, Tilman M. A1 - Groll, Jürgen A1 - Weber, Christian A1 - Liehn, Elisa A. A1 - Koenen, Roy R. T1 - Controlled intramyocardial release of engineered chemokines by biodegradable hydrogels as a treatment approach of myocardial infarction JF - Journal of Cellular and Molecular Medicine N2 - Myocardial infarction (MI) induces a complex inflammatory immune response, followed by the remodelling of the heart muscle and scar formation. The rapid regeneration of the blood vessel network system by the attraction of hematopoietic stem cells is beneficial for heart function. Despite the important role of chemokines in these processes, their use in clinical practice has so far been limited by their limited availability over a long time-span in vivo. Here, a method is presented to increase physiological availability of chemokines at the site of injury over a defined time-span and simultaneously control their release using biodegradable hydrogels. Two different biodegradable hydrogels were implemented, a fast degradable hydrogel (FDH) for delivering Met-CCL5 over 24hrs and a slow degradable hydrogel (SDH) for a gradual release of protease-resistant CXCL12 (S4V) over 4weeks. We demonstrate that the time-controlled release using Met-CCL5-FDH and CXCL12 (S4V)-SDH suppressed initial neutrophil infiltration, promoted neovascularization and reduced apoptosis in the infarcted myocardium. Thus, we were able to significantly preserve the cardiac function after MI. This study demonstrates that time-controlled, biopolymer-mediated delivery of chemokines represents a novel and feasible strategy to support the endogenous reparatory mechanisms after MI and may compliment cell-based therapies. KW - chemokines KW - therapy KW - cardiovascular pharmacology KW - remodelling KW - endothelial progenitor cells KW - left-ventricular function KW - heart-failure KW - rat model KW - recruitment KW - factor-I Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-116597 SN - 1582-4934 VL - 18 IS - 5 ER - TY - THES A1 - Weber, Christian T1 - Bedeutung des Her-2/neu beim Ovarialkarzinom - Korrelation und Vergleich mit klinischen Prognosefaktoren T1 - Meaning of Her-2/neu in ovarian carcinoma - Korrelation and comparison with clinical prognostic factors N2 - In der vorgelegten Arbeit werden klinische Prognosefaktoren des Ovarialkarzinoms an einem Kollektiv von 105 Patientinnen untersucht, die in den Jahren 1996 bis 1998 in der Universitäts-Frauenklinik Würzburg behandelt wurden. Zudem wird eine immunhistochemische Bestimmung des Her-2/neu - Status vorgenommen, der beim Mamma-Karzinom als unabhängiger Prognosefaktor bekannt ist und mit einer schlechteren Prognose einhergeht. Zusammenfassend ließ sich in dieser Arbeit keine Überexpression des Her-2/neu am Ovar feststellen, eine unabhängige prognostische Relevanz muß aus unserer Sicht verneint werden. N2 - In this work we investigated in clinical prognsotic factors of ovarian cancer on patients that were treated because of such a cancer in the Universitäts-Frauenklinik Würzburg from 1996 till 1998. Furthermore we did an immunohistochemical analysis of her-2/neu on ovarian carcinoma, which is known as a significant independent prognostic factor in breast cancer. In conclusion we didn't find an overexpression of her-2/neu in ovarian carcinoma. An independent prognsotic relevance must be denied from our point of view. KW - her-2/neu KW - Ovarialkarzinom KW - prognosefaktor KW - her-2/neu KW - ovarian carcinoma KW - prognsotic significance Y1 - 2005 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-15611 ER -