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Functional validation of T2D dysregulated gene regulatory networks in beta cells
Perturbed islet function is a culprit in Type 2 Diabetes (T2D) and islet research is on the verge of taking a major leap forward thanks to cell type specific information on gene expression using single-cell RNA sequencing (scRNAseq). This has led to identification of genes differentially expressed in each cell type in T2D. However, the field has so far focused on expression differences in single genes, without functional validation, and the contribution to increased understanding of the biological processes affected in T2D islets has been very limited.
To understand the biological processes that are altered in T2D we have developed bioinformatics tools that assess how synchronization of gene expression within entire gene-regulatory networks (GRNs) differs between T2D and control cells, regardless of whether the expression level of each gene is altered. We hypothesize that these GRNs represent the biological processes that are altered in T2D. Using this approach, in addition to unravelling novel biological processes and identifying numerous novel beta cell genes, we have identified GRNs representing most of the experimentally proven beta cell pathophysiology and essentially all genes so far known to be involved in beta cell dysfunction. This fact serves as a positive control that makes us confident that our method can accurately pinpoint the altered characteristics of T2D in each islet cell type.
An important step is to validate the robustness of the method in living cells and animals. Here, I am taking advantage of recent technology advancements, e.g. CROP-seq and whole genome CRISPR screens to test whether the GRNs are functional in living cells. I am also testing whether our method can predict novel regulators of beta cell function that are affected in T2D. With this strategy we are uniquely positioned to resolve the deranged characteristics of T2D at the islet level.
I have 6 years of research experience in the biomedical field, including my current position at the Lund University Research Centre and prior experience as a PhD with a broad understanding of the physiology and biochemistry of metabolic diseases. I hold a Master’s in Molecular and Cellular Biology focused on gene therapy in animal models. I joined the Doctoral Degree in Food Science, Physiology and Health of the Faculty of Pharmacy, University of Navarra to specialize in human physiology and cell biology. In May 2018 I got my PhD with honors (cum laude) and International mention for my studies on the role of oxygen and functional analysis of genes involved in metabolism-related disorders.
Currently, I am working in the functional validation by CRISPR/Cas9 gene editing of transcriptomic data from human islets. The ongoing research is providing me a unique opportunity to extend my research skills and gain technical and management training at a world-leading diabetes research center (Lund University Diabetes Centre) that will reinforce my professional career.