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@PHDTHESIS{Knoll:278045,
      author       = {Knoll, Rainer},
      title        = {{O}mics-driven {D}rug {R}epurposing and {T}reatment
                      {A}ssessment in {H}uman {V}iral {D}iseases},
      school       = {Rheinische Friedrich-Wilhelms-Universität Bonn},
      type         = {Dissertation},
      reportid     = {DZNE-2025-00551},
      pages        = {57 p.},
      year         = {2025},
      note         = {Dissertation, Rheinische Friedrich-Wilhelms-Universität
                      Bonn, 2025},
      abstract     = {In this cumulative thesis, I present my research on
                      transcriptomic-based drug repurposing in human viral
                      infections describing an optimized workflow for drug
                      prediction, in vitro validation and in vivo studies in
                      clinical cohorts based on three publications.In the first
                      publication, I took lead in a larger team effort to
                      introduce a newly designed drug repurposing approach based
                      on whole blood transcriptomics data and drug signatures
                      databases, which was applied to identify potential drug
                      candidates for treatment of patients across COVID-19
                      severity groups stratified based on clinical parameters and
                      transcriptomic phenotypes (Aschenbrenner et al. 2021). One
                      of the drug candidates identified using this approach was
                      dexamethasone, which was predicted to be effective in the
                      most severe group of COVID-19 patients.In the second
                      publication, I present my findings on transcriptomic
                      alterations in the monocyte compartment in chronically
                      infected HIV patients using multi-omics technologies,
                      demonstrate that these alterations originate from a certain
                      disease state and identify potential drug candidates for the
                      reversal of the disease signatures in monocytes (Knoll et
                      al. 2023). In this study, I further extend the
                      transcriptomics drug repurposing approach by refining the
                      underlying disease signatures using single-cell omics for
                      drug prediction and I validate promising drug candidates
                      using in vitro stimulation experiments. Reading out direct
                      drug-induced transcriptional alterations from these in vitro
                      studies substantially strengthened the results from the drug
                      repurposing approach.In the third publication, I describe
                      our framework on how to investigate repurposed drugs in
                      clinical cohorts in vivo using single-cell transcriptomics
                      towards precision medicine, exemplified with dexamethasone
                      treatment in COVID-19 (Knoll et al. 2024). Dexamethasone
                      caused strong transcriptional and immunomodulatory changes
                      with a reversal of dysregulation in severe COVID-19
                      monocytes compared to treatment-naïve patients. Moreover, a
                      treatment-specific monocyte response state was identified
                      which stratified outcome and enabled prediction of treatment
                      responses, stressing the potential of single-cell
                      transcriptomics for companion diagnostics and mechanistic
                      studies of repurposed drugs.In conclusion, the research
                      presented in this thesis describes the design and
                      application of a transcriptomics-based drug repurposing
                      pipeline for human viral infections. It highlights the
                      significant potential of drug repurposing in context of
                      data-driven disease severity stratification using optimized
                      cell-state specific disease signatures. Moreover, it
                      underscores the importance of in vitro validation for
                      promising drug candidates to reverse disease signatures.
                      This paves the way for a standardized analytical approach to
                      evaluate drug indications in clinical cohorts in vivo,
                      utilizing single-cell transcriptomics for treatment response
                      stratification, ultimately enabling precision medicine.},
      cin          = {AG Aschenbrenner / AG Schultze},
      cid          = {I:(DE-2719)5000082 / I:(DE-2719)1013038},
      pnm          = {354 - Disease Prevention and Healthy Aging (POF4-354)},
      pid          = {G:(DE-HGF)POF4-354},
      typ          = {PUB:(DE-HGF)11},
      urn          = {urn:nbn:de:hbz:5-82529},
      url          = {https://pub.dzne.de/record/278045},
}