Kommande disputationer

  • Nezhyva, Mariya

    Integrative Approaches in Shotgun Proteomics: From sample preparation to multifaceted data analysis

    B22, Hushargatan 3, Uppsala 2024-03-15 kl 13:00

    Doktorsavhandling, sammanläggning

    Abstract

    Bottom-up proteomics mass-spectrometry gives an opportunity to shed light on var-ious biological aspects/characteristics such as protein composition, its modifications,interactions, and dynamics. Its applications span a wide range of biological sciencesaiming to eventually answer fundamental disease related questions or evaluate drugperformance and predict adverse effects.

    Bottom-up proteomics experiments are worth the time and effort because it is a comprehensive and multi-level approach to address research questions from a single dataset. Hence, we can gain a thorough understanding of the processes in the studied system and their interconnected changes, thereby confirming results from different perspectives. While the majority of research is focused on the improvement of analytical techniques, it remains challenging to derive meaningful biological insights from the data.

    This Ph.D. thesis contributes to various proteomics challenges, including the development of a high-throughput micro-scale proteomic workflow and comprehensive multifaceted analysis. In particular, the data on the thermal proteome profiling of melanocyte-stimulating hormone interactions with melanocortin receptors was analyzed using a newly developed workflow. This workflow uniquely combines thermal stabilization data, inferred transcription factor activity, and pathway analysis. Additionally, this thesis integrates omics approaches such as metabolomics and proteomics. Another dimension to the dataset was added by combining metabolic mass spectrometry imaging with region-specific proteomics for the characterization of cocaine’s neurotoxicity.

    Open access
  • Faraj, Alan

    Pharmacometric models to inform dose selection and study design: Applied in hemophilia and tuberculosis

    room A1:107a, BMC, Husargatan 3, Uppsala 2024-03-08 kl 13:15

    Doktorsavhandling, sammanläggning

    Abstract

    While tuberculosis is a global pandemic, hemophilia is a rare disease which many have not heard of. Due to tuberculosis mainly being a problem in developing countries and hemophilia being a rare disease, they are not as heard of as other diseases such as cancer or metabolic diseases which are on the rise in Western societies. The quality of life for patients suffering from these diseases is notably impaired and novel drugs are warranted to further improve the treatment and management of both diseases. As market incentives are a limiting factor, it is important that the efforts that are taken to develop novel drugs are carried out in an informative manner.   One strategy to incorporate as much information as possible to inform decision making in drug development is to use pharmacometric methods. Such strategies enable simultaneous analysis of different types of data that are generated during drug development programs. In this thesis, the aim was to develop and apply pharmacometric models to facilitate dose selection and study designs in clinical programs that aim at developing new drugs for tuberculosis and hemophilia.   A standardized analysis approach of early clinical trials studying drugs against tuberculosis was presented including power calculations that showed the number of patients needed to detect drug effects. Such efforts are important as showing drug effect in early trials will aid decision making into significantly longer and costlier late trials. The approach was used to analyze a clinical trial studying if the current dose of meropenem can be lowered without negatively impacting drug effects and improving the already poor tolerability of the drug. The study found that lowering the dose may lower activity without any improvement of the tolerability properties. Furthermore, population pharmacokinetic models were developed for two novel hemostatic drugs in development for prophylactic and on-demand treatment of hemophilia. Based on the models, clinical trials in adult and pediatric subjects were supported. One of the trials were performed and it was showed with a model-based analysis that the new drug which is given subcutanously has similar efficacy as current intravenously given standard of care alternatives. Using the developed models, different strategies for designing pharmacokinetic trials in children was also presented.   In conclusion, the work performed within this thesis has contributed to the development of new drugs against tuberculosis and hemophilia.

    Open access
Senast uppdaterad: 2023-06-13