@phdthesis{Koike2023,
  author    = {Koike, Akito},
  title     = {Molekular und zellbiologischer Ansatz hin zu neuartigen Medikamenten gegen \(Echinococcus\) \(multilocularis\)},
  doi       = {10.25972/OPUS-28864},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-288649},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2023},
  abstract  = {Echinococcosis is an important zoonosis. The causative agent of Alveolar Echinococcosis (AE) is Echinococcus multilocularis. The treatment of human AE is limited to surgery and chemotherapy with albendazole (ABZ). However, ABZ works only parasitostatically and it needs to be taken for long periods, although it causes adverse side effects. Thus, development of new, parasiticidal drug with selective toxicity is required. Because undifferentiated stem cells of E. multilocularis play key role in its longevity and regenerative capacity, targeting stem cells is especially important. In vitro screening of protein kinases inhibitors demonstrated that human PIM kinases inhibitors have detrimental effects on E. multilocularis. Through yeast two hybrid assay, the interaction of parasite PIM kinase (EmPIM) and its CDC25 (EmCDC25) was indicated. Through in situ hybridization, expression of EmPIM in the stem cells was observed. Therefore, EmPim is likely to be a positive regulator of cell cycle progression, the same as human Pim1. In addition, 20 compounds against EmPIM were selected through in silico screening and synthesized. One of them has a detrimental effect on E.multilocularis comparable to human pan-PIM inhibitors, but has much weaker toxicity on human cell lines. Furthermore, triclabendazole (TCBZ) and its metabolite TCBZSX, which are approved for another flatworm disease, Fascioliasis were tried on E. multilocularis. With two stem cell markers, damage to stem cells by TCBZSX was shown. In addition, primary cells from treated vesicles never regenerated and the damage to stem cells proved to be irreversible. Our in silico screening method used in EmPIM research has potential to identify compounds which overcome the side effect problem in ABZ-based chemotherapy. On the other hand, it is expected that my research of TCBZ can lead to development of a practical parasiticidal chemotherapy by combining TCBZ, which damages stem cells, and ABZ, which damages differentiated cells.},
  subject      = {Bandw{\"u}rmer},
  language  = {en}
}
@phdthesis{Mottola2021,
  author    = {Mottola, Austin},
  title     = {Molecular characterization of the SNF1 signaling pathway in \(Candida\) \(albicans\)},
  doi       = {10.25972/OPUS-23809},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-238098},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2021},
  abstract  = {The fungus Candida albicans is a typical member of the human microbiota, where it usually behaves as a commensal. It can also become pathogenic; often causing minor superficial infections in healthy people, but also potentially fatal invasive systemic infections in immunocompromised people. Unfortunately, there is only a fairly limited set of antifungal drugs, and evolution of drug resistance threatens their efficacy. Greater understanding of the mechanisms that C. albicans uses to survive in and infect the host can uncover candidate targets for novel antifungals. Protein kinases are central to a vast array of signalling pathways which govern practically all aspects of life, and furthermore are relatively straightforward to design drugs against. As such, investigation and characterization of protein kinases in C. albicans as well as their target proteins and the pathways they govern are important targets for research. AMP-activated kinases are well conserved proteins which respond to energy stress; they are represented in yeasts by the heterotrimeric SNF1 complex, which responds primarily to the absence of glucose. In this work, the SNF1 pathway was investigated with two primary goals: identify novel targets of this protein kinase and elucidate why SNF1 is essential. Two approaches were used to identify novel targets of SNF1. In one, suppressor mutants were evolved from a strain in which SNF1 activity is reduced, which exhibits defects in carbon source utilization and cell wall integrity. This revealed a suppressor mutation within SNF1 itself, coding for the catalytic subunit of the complex - SNF1Δ311-316. The second approach screened a library of artificially activated zinc cluster transcription factors, identifying Czf1 as one such transcription factor which, upon artificial activation, restored resistance to cell wall stress in a mutant of the SNF1 pathway. Finally, a, inducible gene deletion system revealed that SNF1 is not an essential gene.},
  subject      = {candida albicans},
  language  = {en}
}
@phdthesis{Dinev2001,
  author    = {Dinev, Dragomir},
  title     = {Analysis of the role of extracellular signal regulated kinase (ERK5) in the differentiation of muscle cells},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-1180481},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2001},
  abstract  = {The MEK5/ ERK5 kinase module is a relatively new discovered mitogen-activated protein kinase (MAPK) signalling pathway with a poorly defined physiological function. Since ERK5 and its upstream activator MEK5 are abundant in skeletal muscle a function of the cascade during muscle differentiation was examined. ERK5 becomes activated upon induction of differentiation in mouse myoblasts. The selective activation of the pathway results in promoter activation of differentiation-specific genes, such as the cdk-inhibitor p21 gene, the myosin light chain (MLC1A) gene, or an E-box containing promoter element, where myogenic basic-helix-loop-helix proteins such as MyoD or myogenin bind. Moreover, myogenic differentiation is completely blocked, when ERK5 expression is inhibited by antisense RNA. The effect can be detected also on the expression level of myogenic determination and differentiation markers such as p21, MyoD and myogenin. Another new finding is that stable expression of ERK5 in C2C12 leads to differentiation like phenotype and to increased p21 expression levels under growth conditions. These results provide first evidence that the MEK5/ERK5 MAP kinase cascade is critical for early steps of muscle cell differentiation.},
  subject      = {Muskelzelle},
  language  = {en}
}