202 Chapter 7 This thesis focuses on the development of new in vitro and in silico translational models to study two diseases affecting fatty acid metabolism. Liver and intestinal organoids are presented as suitable tools to study malnutrition and medium-chain acyl-CoA dehydrogenase deficiency (MCADD). Moreover, I also present two in silico models that helped compliment the findings of the in vitro systems as well as to predict metabolic responses. During the thesis, I also focused on the effects of both diseases on peroxisomal and mitochondrial homeostasis and their interplay. In this chapter, I focus on (i) a general discussion about different aspects related to these new translational models and (ii) the importance of the peroxisomalmitochondrial interplay in health and disease. PART 1. ESTABLISHING TRANSLATIONAL IN VITRO AND IN SILICO MODELS FOR THE STUDY OF MALNUTRITION AND MCADD In this thesis, I established two in vitro organoid models to study malnutrition and medium chain acyl-CoA dehydrogenase deficiency. I have also focused on the development of two in silico models. First, I developed a detailed kinetic model to study fluxes and metabolite concentrations of the peroxisomal β-oxidation. Secondly, I contributed to the development of a deep learning (DL) model to measure and track organoid size. This was done by providing data, defining requirements and validating the outcomes. In this section, I discuss about the establishment of these models for the study of the abovementioned diseases and how to tailor them to metabolic research. Next, I highlight the limitations of these models and focus on the potential approaches and optimizations needed to overcome these limitations. Applications and advantages of translational models for metabolic research In chapter 2, I focused on the development of two in vitro models to study malnutrition. These models were established using primary tissue from murine liver and intestine to set up hepatic and intestinal organoids respectively. To the best of our knowledge, these are the first hepatic and intestinal organoid models of malnutrition described. A variation of the intestinal model was recently described in the literature to understand the role of mitochondrial homeostasis and intestinal barrier function1. More recently, human intestinal organoids have also been established for the study of malnutrition in vitro2.
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