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Impact of Altered Myofilament Calcium Sensitivity on the Susceptibility to and Maintenance of Atrial Fibrillation Episodes
No full textPromotionskolleg für Medizinstudierende der Universitätsmedizin GöttingenVorhofflimmern stellt die häufigste atriale Arrhythmie dar und zeigt eine altersabhängig zunehmende Inzidenz. Oft erfolgt die Diagnose erst in Zusammenhang mit Komplikationen wie Schlaganfällen oder Herzinsuffizienz. Da Vorhofflimmern mit einer erhöhten Mortalität und Morbidität assoziiert ist, stellt eine adäquate Therapie eine wichtige Grundlage zur Reduktion dieser Folgen dar. Oft weisen die antiarrhythmischen Medikamente erhebliche Einschränkungen in Bezug auf ihre Wirksamkeit und Sicherheit auf, weshalb es wichtig ist, die Mechanismen zur Entstehung von Vorhofflimmern zu identifizieren und mögliche Therapieansätze hierfür zu finden. Studien konnten bereits zeigen, dass die Entstehung und Aufrechterhaltung von Vorhofflimmern mit einer veränderten Calciumpufferung einhergeht. Die vorliegende Arbeit beschäftigt sich deshalb mit der Frage, ob eine erhöhte oder erniedrigte Calciumpufferung zu einem vermehrten Auftreten und einer Aufrechterhaltung von Vorhofflimmern beiträgt. Hierzu wurden murine Herzen am Langendorff-System perfundiert und mit Hilfe von elektrischer Stimulation sowie spezifischer Pacing Protokolle atriale Arrhythmien ausgelöst. Die extrazelluläre Kaliumkonzentration wurde schrittweise reduziert, um die Arrhythmieanfälligkeit der Herzen zu erhöhen. Zur Untersuchung der Auswirkung einer erniedrigten Calciumpufferung auf die Anfälligkeit und Aufrechterhaltung von atrialen Arrhythmien wurde Blebbistatin verwendet. Hier zeigte sich während der Perfusion mit einer 2 mM Kalium- und 300 μM Diazoxid-Lösung eine signifikant höhere Induzierbarkeit atrialer Arrhythmien sowie eine Tendenz zu längeren Arrhythmieepisoden in der Blebbistatin-Gruppe. Levosimendan wurde als Calcium-Sensitizer eingesetzt, um die Auswirkungen einer erhöhten Calciumpufferung zu untersuchen. Auch hier zeigte sich unter den selben Bedingungen ein signifikanter Unterschied in der Induzierbarkeit der atrialen Arryhthmien. Um mögliche Effekte durch die Hemmung der Phosphodieserase des Typ III von Levosimendan auszuschließen, wurden Versuche an einer Mauslinie mit einer heterozygoten Myosin-binding-protein-C3-Genmutation durchgeführt. Hierbei zeigte sich erneut die Tendenz für eine höhere Induzierbarkeit von Arrhythmien gegenüber der Kontroll-Gruppe sowie eine signifikant höhere Episodendauer unter physiologischen Kaliumkonzentrationen. Die Ergebnisse dieser Arbeit weisen darauf hin, dass sowohl eine erhöhte als auch eine erniedrigte Calciumpufferung die Entstehung von Vorhofflimmern begünstigen kann und zu dessen Aufrechterhaltung beiträgt. Die gezielte Modulation der Calciumpufferung könnte daher einen potentiellen therapeutischen Ansatz zur Behandlung und Prävention von Vorhofflimmern darstellen und sollte in zukünftigen Studien weiter untersucht werden.Atrial fibrillation is the most common atrial arrhythmia and shows an age-dependent increase in incidence. In many cases, diagnosis is only made after the occurrence of complications such as stroke or heart failure. Since atrial fibrillation is associated with increased mortality and morbidity, appropriate therapy is essential to reduce these consequences. Antiarrhythmic drugs often present significant limitations regarding their efficacy and safety, which highlights the importance of identifying the mechanisms underlying the development of atrial fibrilation and to find potential therapeutic strategies. Previous studies have demonstrated that the initiation and maintenance of atrial fibrillation are associated with altered calcium buffering. This work therefore addresses the question of whether increased or decreased calcium buffering contributes to the occurrence and persistence of atrial fibrillation. For this purpose, murine hearts were perfused using the Langendorff system and atrial arrhythmias were induced via electrical stimulation as well as specific pacing protocols. The extracellular potassium concentration was gradually reduced to increase the susceptibility of the hearts to arrhythmias. To investigate the effect of reduced calcium buffering on the susceptibility to and maintenance of atrial arrhythmias, Blebbistatin was applied. During perfusion with a solution containing 2 mM potassium and 300 μM diazoxide, a significantly higher inducibility of atrial arrhythmias, as well as a tendency toward longer arrhythmia episodes, was observed in the Blebbistatin group. Levosimendan was used as a calcium sensitizer to examine the effects of increased calcium buffering. Under the same conditions, a significant difference in arrhythmia inducibility was also observed. To evaluate potential effects due to phosphodiesterase type III inhibition by Levosimendan, additional experiments were conducted in a mouse line with heterozygous mutation in the myosin-binding-protein-C3-gene. Here, once again, a tendency toward higher arrhythmia inducibility compared to the control group was observed, as well as a significantly longer arrhythmia duration under physiological potassium concentrations. The results of this study suggest that both increased and decreased calcium buffering may promote the initiation and maintenance of atrial fibrillation. Targeted modulation of calcium buffering could therefore represent a potential therapeutic approach for the treatment and prevention of atrial fibrillation and should be investigated in future studies.10000-01-01Diese Dateien sind bis zum Abschluß der Staatsexamensprüfung gesperrt.These files are not accessible until the state exam has been completed
The Politics of Dance and The Poetics of Space: Kurdish Dances in Germany
No full textAus urheberrechtlichen Gründen wird die Zusammenfassung der Arbeit nicht online angezeigt.Due to intellectual property rights the abstract of this work is not availabe online.2023-05-3010000-01-01Das PDF ist bis auf weiteres gesperrt
Regulation of binding of HP1 associated complexes to chromatin and their role in transcription regulation in C. elegans vulva development
No full textHP1 proteins are known to bind to H3K9me3 and thereby localize to heterochromatin. However, direct functions of HP1 in heterochromatin formation and maintenance are not clear. This is partially due to essentiality of HP1 proteins in mammals and flies. We therefore, explored the functions of HP-1 homologues in C. elegans.
Our findings suggest that the C. elegans HP1 homologue; HPL-2 does not directly bind H3K9me3, unlike what has been proposed for HP1 family proteins. Interestingly, HPL-2 depends on LIN-61 for association with H3K9me3. Our analysis of LIN-61-H3K9me3 interaction defective mutant suggests that HPL-2-LIN-61-H3K9me3 interaction is required for vulva development in C. elegans.
We further demonstrate that HPL-2, LIN-61 and LIN-13 biochemically interact with each other to form multiple complexes. We show that HPL-2 interacts with both LIN-61 and LIN-13 via its CSD. Moreover, we show that LIN-61 and LIN-13 do not directly interact with each other in the absence of HPL-2. Consequently, full length HPL-2 and possibly its multimerization is required for LIN-61-HPL-2-LIN-13 complex formation.
Our results suggest existence of at least three putative complexes among HPL-2, LIN-13 and LIN-61. These complexes bind distinct, non-overlapping subsets of target genes and regulate their transcription including genes associated with vulva development. In agreement, hpl-2, lin-61 and lin-13 genetically interact with each other during vulva development.
Analysis of the binding sites of HPL-2-LIN-61 complex and HPL-2-LIN-13 complex reveals two distinct modes of chromatin association of HPL-2. Sharp distribution of HPL-2-LIN-13 complex points to transcription factor mediated recruitment. Broad distribution of HPL-2-LIN-61 complex points to ncRNA mediated recruitment. Our results on involvement of a RNA component in the stability of HPL-2-LIN-61-LIN13 complexes reiterate our findings.
Overall, our studies highlight the role of HP1 associated complexes in transcription regulation in vulva development in C. elegans
6-thioguanine–induced changes in the proteome and their dependence on mismatch repair status in colon carcinoma cells
No full textStrukturschäden an der DNA, zu denen auch Fehlpaarungen von Basen zählen, können durch mutagene Einwirkungen oder aber spontan entstehen. Zu einem gewissen Grad können diese vom Mismatch-Reparatur-System (MMR) repariert werden oder aber zum Zelltod führen, welcher unter anderem bei den antineoplastischen Purinanaloga wie 6-Thioguanin (6-TG) eine gewünschte Wirkweise darstellt. Einige Karzinom-Entitäten wie das Kolonkarzinom sind mit einem Funktionsverlust von Proteinen des MMR assoziiert. Unser Ziel war es den Einfluss von MLH1 als einen der Hauptrepräsentanten des Mismatch-Reparatursystems im Hinblick auf das Therapieansprechen von Thiopurinen auf Proteinebene zu untersuchen.
Hierzu wurden zwei isogene Zellgruppen der RKO-Zelllinie so etabliert, dass die Wildtype Zellen eine natürliche Defizienz am MLH1 Gen aufwiesen (MLH1–), während einigen von ihnen das Gen wieder ins Genom eingebaut wurde (MLH1+). Beide Zellgruppen wurden dann mit 6-TG behandelt, es folgte ein quantitativer Proteinvergleich mittels zweidimensionale Gelelektrophorese (2DGE). Unterschiedlich regulierte Proteine wurden massenspektrometrisch identifiziert und bezüglich deren Beteiligung an verschiedenen biologischen Funktionen analysiert. Die gefundenen Proteine wurden mit Hilfe der STRING Bioinformatik-Datenbank (www.string-db.org) auf deren Beteiligung an biologischen Prozessen untersucht.
Die Etablierung des isogenen Zellpaares, welches sich nur in der Expression von MLH1 unterscheidet, wurde mittels Western Blot nachgewiesen. In der 2DGE ergaben sich insbesondere signifikante Unterschiede in den Gruppen MLH1+ nach 6-TG-Behandlung im Vergleich zu MLH1– nach Behandlung mit 6-TG. Massenspektrometrisch konnte erstmalig auf Proteomebene aufgezeigt werden, welche Proteine sich zwischen den Zellgruppen quantitativ unterscheiden. Durch die Anwendung der STRING-Analyse zeigt sich insbesondere eine Beteiligung in jenen biologischen Prozessen, die im Purinmetabolismus beteiligt sind; darüber hinaus in der Regulation von Zelltod und in biologischen Prozessen, die als Antwort auf oxidativen Stress gedeutet werden können.
Da Proteine, die in den Apoptose-Signalwegen involviert sind, vermehrt nach 6-TG-Behandlung besonders bei MLH1+ Zellen zu beobachten waren, wurde die Hypothese aufgestellt, dass durch 6-TG-Behandlung insbesondere bei MLH1+ Zellen ein Zelluntergang induziert wird. Dies wurde mittels Western Blotting mit p53 überprüft und konnte verifiziert werden: es ließ sich ein signifikant erhöhtes Signal bei 6-TG-behandelten MLH1+ Zellen, nicht jedoch bei MLH1– Zellen messen. Ebenfalls mittels Western Blots wurde die Beobachtung verifiziert, dass besonders nach 6-TG-Gabe GSTP1 als eines der Proteine, die in der Antwort auf oxidativen Stress beteiligt sind, hochreguliert wird und dies deutlicher in MLH1– Zellen als in MLH1+ Zellen. Hier besteht weiterer Forschungsbedarf, um diese Beobachtung mit anderen Methoden zu verifizieren und Erklärungen hierfür zu finden. Insbesondere, da eine erhöhte GSTP1-Expression bei mehreren Tumorentitäten mit Therapieresistenz und schlechterer Prognose assoziiert ist.
Das Patientenkollektiv, welches bereits somatisch ein defizientes MMR (dMMR) aufweist und eine Indikation für Azathioprin hat, dürfte klein sein. Dennoch könnte es für diese Patienten entscheidend sein eine dMMR zu identifizieren und gegebenenfalls auf alternative Therapien auszuweichen, wie beispielsweise bei Rektumkarzinom-Patienten, bei denen man inzwischen bei dMMR bereits auf die etablierte Erstlinienchemotherapie mit 5-Flurouracil als Antimetabolit verzichtet und stattdessen auf eine Immuntherapie setzt.Structural damage to the dna, including base mismatches, can arise either from mutagenic influences or spontaneously. To a certain extent, such damage can be repaired by the mismatch repair (MMR) system or may instead lead to cell death, which represents a desired mechanism of action for antineoplastic purine analogues such as 6-thioguanine (6-TG). Certain carcinoma entities, such as colon carcinoma, are associated with a loss of function of MMR proteins. The aim of this study was to investigate the influence of MLH1, as one of the main components of the mismatch repair system, on the therapeutic response to thiopurines at the proteomic level.
Two isogenic cell populations of the RKO cell line were established: the wild-type cells exhibited a natural deficiency of the MLH1 gene (MLH1−), while in a subset of these cells the gene was reintroduced into the genome (MLH1+). Both cell populations were then treated with 6-TG, followed by a quantitative protein comparison using two-dimensional gel electrophoresis (2DGE). Differentially regulated proteins were identified by mass spectrometry and analyzed with regard to their involvement in various biological functions. The identified proteins were examined for their participation in biological processes using the STRING bioinformatics database (www.string-db.org).
The successful establishment of the isogenic cell pair, differing only in MLH1 expression, was confirmed by Western blotting. In 2DGE analyses, significant differences were observed particularly in the MLH1+ groups after 6-TG treatment compared with MLH1− cells treated with 6-TG.
For the first time, mass spectrometry enabled at the proteomic level the identification of proteins that differ quantitatively between the cell groups. STRING analysis revealed a pronounced involvement of these proteins in biological processes associated with purine metabolism, as well as in the regulation of cell death and in processes that can be interpreted as responses to oxidative stress.
Since proteins involved in apoptotic signaling pathways were more frequently observed after 6-TG treatment, particularly in MLH1+ cells, the hypothesis was formulated that 6-TG treatment induces cell death predominantly in MLH1+ cells. This hypothesis was tested by Western blotting for p53 and could be confirmed: a significantly increased signal was detected in 6-TG-treated MLH1+ cells, but not in MLH1− cells. Western blot analyses also verified the observation that, particularly after 6-TG treatment, GSTP1, as one of the proteins involved in the response to oxidative stress, was upregulated more markedly in MLH1− cells than in MLH1+ cells. Further research is required to validate this observation using additional methods and to elucidate the underlying mechanisms, especially since increased GSTP1 expression is associated with therapy resistance and poorer prognosis in several tumor entities.
The patient population that already exhibits somatic deficient MMR (dMMR) and has an indication for azathioprine therapy is likely to be small. Nevertheless, identifying dMMR may be crucial for these patients in order to consider alternative therapeutic strategies, as is now practiced in rectal carcinoma patients, where in cases of dMMR the established first-line chemotherapy with the antimetabolite 5-fluorouracil is omitted in favor of immunotherapy.2027-02-1
Deciphering the molecular mechanisms determining spore type-specific development and pathogenicity in Colletotrichum graminicola
No full textColletotrichum graminicola is a hemibiotrophic fungal pathogen that causes
anthracnose disease in Zea mays (maize). This pathogen produces two distinct
types of asexual spores: falcate and oval conidia, each specialized for generating
different secondary metabolites, unique developmental processes, and distinct
infection strategies. Falcate conidia are formed in acervuli and play a key role in
disease dissemination, whereas oval conidia are typically found in the parenchyma
cells close to the plants vascular system, and are responsible for systemic infection
through roots (Rudolph et al. 2024, Rudolph et al. 2025). Despite their distinct
functions, the molecular mechanisms governing these spore type-specific behaviors
remain largely unexplored. Thus, this study focuses on identifying the key factors
shaping the spore type-specific vegetative and pathogenic development, to gain a
deeper understanding of the intricate interactions between C. graminicola and its
host plant, Zea mays.
The first project presents a comparative RNA-seq analysis to uncover the genetic
mechanisms driving the distinct biological characteristics of different spore types of
C. graminicola, with a focus on germination, germling fusion, and early leaf infection.
Our analysis revealed that freshly harvested falcate and oval conidia exhibit unique
gene expression profiles. Overall, both spore types shared 1,651 upregulated and
1,884 downregulated genes compared to mycelium samples, but also had unique
sets of upregulated (1,449 for oval and 1,874 for falcate conidia) and downregulated
genes (1,213 for oval and 1,474 for falcate conidia), highlighting the distinct
metabolic activities and differences between these spore types. During the
developmental stages, we identified several genes that regulate development,
which are either upregulated in both spore types or are specific for one of the spore
type. Similarly, we observed distinct gene expression patterns in leaves infected by
falcate and oval conidia, particularly concerning the induction of effector genes, the
repertoire of carbohydrate-active enzymes (CAZymes), and membrane transporters
during early leaf infection. Overall, these findings provide new insights into the
genetic mechanisms underlying the development and pathogenicity of
C. graminicola spore types.
The second project summarizes our findings regarding the role of secondary
metabolite mycosporine glutamine in inhibiting the germination of falcate conidia.
Our results indicate that the deletion of genes likely involved in mycosporine
glutamine biosynthesis leads to the induction of germination and germling fusion
between falcate conidia, thereby confirming both the existence of these genes
(Cgatp-grasp, Cgo-met, and Cgdhqs) and the pathway for mycosporine glutamine
production in C. graminicola. Further, the role of these genes in mycosporine
glutamine biosynthesis was also confirmed by HPLC analysis. However, the
inhibition of germination was not completely lifted, which raises questions about the
possible involvement of other germination inhibitors that could be influencing the
observed effects on falcate conidia. Furthermore, our experiments demonstrated
that mycosporine glutamine does not affect the formation of infection structures
needed for pathogenicity. This suggests that there are additional factors within the
extracellular matrix of conidia that can influence spore behavior, directing them
either towards vegetative growth or pathogenic development.2027-01-1
Biocompatible Nanostructures from Stimuli-Responsive Self-Assembly of Peptides and Peptide Hybrids
No full textThis doctoral thesis dwells on the synthesis and characterization of biocompatible nanostructures generated by stimuli-responsive self-assembly of peptides and peptide hybrids. Five different chapters highlight different research projects. In particular, we focused on the synthesis and introduction of photoswitches and photocages into peptide strands to induce structural modification that would ultimately lead to interstrand interactions and self-assembly processes. We proceeded to characterize the chemical and physical characteristics of such photomolecules by UV- and CD-spectroscopy. Further structural studies were carried out either via NMR techniques or by imaging with CryoEM. Biological applications were also investigated, for the use of such molecules as probes for imaging techniques such as fluorescence microscopy multiplexing.2026-02-202027-02-20Vorläufig gesperr
Prognostische Bedeutung von Thoraxschmerzen bei akuter Lungenarterienembolie
No full textAcute pulmonary embolism (PE) is a common and potentially life-threatening cardiovascular disease associated with significant morbidity and mortality. Chest pain is a frequent symptom in patients with acute PE. Previous studies suggested a possible association between chest pain and improved clinical outcomes; however, the prognostic relevance and underlying mechanisms remain insufficiently understood.
This study aimed to evaluate the prognostic significance of chest pain in patients with acute pulmonary embolism and to investigate whether differences in initial clinical management may contribute to potential outcome differences.
Data were analyzed from the Pulmonary Embolism Registry Göttingen, a prospective single-center cohort study. Patients with confirmed symptomatic acute PE between 2008 and 2019 were included. The primary endpoint was the occurrence of PE-related complications during hospitalization. The secondary endpoint was all-cause in-hospital mortality.
A total of 858 patients were included in the analysis. Chest pain was present in approximately half of the patients at diagnosis. Patients presenting with chest pain were younger and had fewer comorbidities. Chest pain was associated with significantly lower rates of PE-related complications and lower in-hospital mortality. Multivariable analyses confirmed the independent association between chest pain and favorable in-hospital outcome. Differences in emergency management, including higher rates of prehospital medical contact and earlier anticoagulation, did not explain this association.
Chest pain in patients with acute pulmonary embolism is associated with a more favorable in-hospital outcome. This association is likely related to differences in patient characteristics rather than differences in clinical management. Chest pain may represent a clinical marker of lower disease severity. Further multicenter studies are needed to clarify the underlying mechanisms and to evaluate the potential integration of chest pain into risk stratification models.2027-02-0
Combined Inhibition of Heat Shock Protein 90 and Cyclin-Dependent Kinases 4 and 6: Advancing Therapeutic Strategies in Pancreatic Ductal Adenocarcinoma
No full textGöttinger Promotionskolleg für Medizinstudierende, Else Kröner-Fresenius-KollegPancreatic ductal adenocarcinoma is one of the most aggressive and deadly cancer types, with current therapies failing to significantly prolong life expectancy. Heat shock factor 1 (HSF1) and heat shock protein 90 (HSP90) are frequently upregulated in cancer cells, making them attractive therapeutic targets. However, the clinical efficacy of HSP90 inhibitors has been limited, partly due to induction of a compensatory heat shock response mediated by HSF1.
This thesis investigated a combinatorial treatment strategy to enhance HSP90 inhibition by suppressing HSF1 activity through cyclin-dependent kinase 4 and 6 (CDK4/6) inhibition. Commercial and patient-derived pancreatic ductal adenocarcinoma cell lines were treated with the CDK4/6 inhibitor Palbociclib and the HSP90 inhibitor Ganetespib, alone and in combination. Transcriptional changes were analyzed using quantitative real-time polymerase chain reaction and ribonucleic acid sequencing. Immunoblot analysis was performed to determine protein levels. Functional aspects of the treatment were assessed through cell viability assay, cell death assay and confluence measurements.
This thesis demonstrates that the combined inhibition of CDK4/6 and HSP90 effectively suppresses HSF1 activity and mitigates the heat shock response, a major limitation to monotherapies with HSP90 inhibitors. The combinatorial treatment relevantly impairs cancer cell viability, induces cell death and destabilizes key pro-oncogenic proteins. These findings provide a strong rationale for further preclinical and clinical evaluation of this approach to improve therapeutic outcomes in patients with pancreatic ductal adenocarcinoma.2027-02-1
A Randomized, Blinded, Placebo-Controlled Preclinical Study on the Antifibrotic and Nephroprotective Effects of Combination Therapy with the Monoclonal Antibody Actinab and the ACE Inhibitor Ramipril in the Alport Mouse Model
No full textBeim Alport-Syndrom handelt es sich um eine hereditäre Kollagen Typ IV Erkrankung, die zu einer Beeinträchtigung der glomerulären Filterfunktion der Niere führt. Die derzeitige Standardtherapie ist die frühzeitige Gabe eines ACE-Hemmers. Die Therapie mit dem ACE-Hemmer Ramipril wurde im Rahmen dieser Studie placebokontrolliert am COL4A3-knockout Alport-Mausmodell um einen das Aktinzytoskelett der Podozyten stabilisierenden monoklonalen Antikörper, Actinab, ergänzt. Verglichen wurden die COL4A3-knockout Mäuse zudem mit Wildtypmäusen als gesunde Kontrollen, die auch entweder Actinab oder ein Placebo erhielten, nicht jedoch Ramipril. Als Endpunkte wurden die Überlebensdauer der Mäuse, der Verlauf der Proteinurie, die histologischen Veränderungen der Nieren anhand von Laminin- und Fibronektin-Immunfluoreszenzfärbungen, sowie der Verlauf der Serum-Cholesterin- und Serum-Harnstoffwerte gewählt, wobei die gesunden Kontrollen nicht hinsichtlich des Überlebens untersucht wurden. Die Ergebnisse zeigen keine statistisch signifikanten Unterschiede bezüglich des Überlebens (p=0,473) und der Albuminurie (p=0,189) zwischen der Placebo- und der Wirkstoffgruppe. Bei den Fibronektin-Immunfluoreszenzfärbungen findet sich ein statistisch signifikanter Unterschied bezogen auf die Vernarbung der Nieren bei Mäusen im Alter von neun Wochen zwischen der erkrankten Placebogruppe und der Actinab erhaltenden (p=0,024) bzw. der Placebo erhaltenden Wildtypgruppe (p=0,047). Für die Anreicherung von Bindegewebe zeigen sich in der Laminin-Immunfluoreszenzfärbung nur teilweise statistisch signifikante Unterschiede zwischen den gesunden Wildtypgruppen sowie den erkrankten Placebo- und Wirkstoffgruppen. Für die Cholesterinwerte lassen sich keine statistisch signifikanten Unterschiede feststellen, was gegen eine pro-nephrotische Wirkung der Kombinationstherapie spricht. Die Harnstoffwerte zeigen bei den sieben Wochen alten Mäusen statistisch signifikante Unterschiede zwischen den gesunden Wildtypgruppen und den beiden erkrankten Kombitherapiegruppen (p<0,050). Hingegen ergeben sich bei den neun Wochen alten Mäusen nur statistisch signifikante Unterschiede zwischen den gesunden Wildtypgruppen und der Placebogruppe (p=0,040 bzw. p=0,034). Es wäre also möglich, dass sich die Harnstoffelimination im Verlauf unter der Kombinationstherapie mit Ramipril und Actinab bessert. Zusammenfassend sind die Auswirkungen der Kombinationstherapie mit Ramipril und Actinab sowohl bezüglich des Überlebens, als auch bezüglich der Albuminurie und des Serum-Cholesterins nicht statistisch signifikant. Ein möglicher positiver Effekt auf die Harnstoffelimination sowie die histologischen Outcomes bedarf weiterer Untersuchungen.Alport syndrome is a hereditary disorder of type IV collagen that leads to impaired glomerular filtration function in the kidneys. The current standard treatment is early administration of an ACE inhibitor. In this study, therapy with the ACE inhibitor Ramipril was supplemented with Actinab, a monoclonal antibody that stabilizes the actin cytoskeleton of podocytes, in a placebo-controlled trial using the COL4A3 knockout Alport mouse model. The COL4A3 knockout mice were also compared with wild-type mice as healthy controls, which received either Actinab or a placebo, but not Ramipril. The selected endpoints were the survival time of the mice, the progression of proteinuria, histological changes in the kidneys based on laminin and fibronectin immunofluorescence staining, and the progression of serum cholesterol and serum urea levels. The healthy controls were not examined in terms of survival. The results show no statistically significant differences in survival (p=0.473) and albuminuria (p=0.189) between the placebo and active substance groups. Fibronectin immunofluorescence staining revealed a statistically significant difference in renal scarring in nine-week-old mice between the diseased placebo group and the actinab-treated wild-type group (p=0.024) as well as the placebo-treated wild-type group (p=0.047). For connective tissue enrichment, laminin immunofluorescence staining shows only partially statistically significant differences between the healthy wild-type groups and the diseased placebo and active substance groups. No statistically significant differences can be observed for cholesterol levels, which argues against a pro-nephrotic effect of the combination therapy. Urea levels in seven-week-old mice show statistically significant differences between the healthy wild-type groups and the two diseased combination therapy groups (p<0.050). In contrast, in nine-week-old mice, statistically significant differences are only found between the healthy wild-type groups and the placebo group (p=0.040; p=0.034). It is therefore possible that urea elimination improves over the course of combination therapy with Ramipril and Actinab. In conclusion, the effects of combination therapy with Ramipril and Actinab are not statistically significant in terms of survival, albuminuria, or serum cholesterol. A possible positive effect on urea elimination and histological outcomes requires further investigation.2027-01-2