
There are no projects in the garbage can.
Most chronic diseases are complex having multiple factors behind their pathogenesis. Most immune mediated diseases are considered inflammatory with processes that may begin through infections, activation of the innate immune system, the adaptive immune system and the immunopathology that while attempting to restore tissue produces tissue damage. The group of Marta Alarcón- Riquelme has focused for years in understanding the genetic of the autoimmune or immune-mediated disease systemic lupus erythematosus and later on the role of various genomic and epigenomic markers that modulate gene expression and functionality of the genetic variants associated with disease. More recently she has been using machine learning to design predictive models of treatment responses using multi-omics integration. Her group has discovered several genes involved in the susceptibility to develop systemic lupus erythematosus. One of the genes, Bank1 has as primary function and impact on B cells that are implicated in the overproduction of specific populations of B cells that infiltrate the kidney, producing autoantibodies leading to kidney damage. In order to understand gene function, the group has been working with preclinical mouse models of disease making use of single cell RNA sequencing to understand which B cell development trajectories the gene impacts on.
Through genotyping, deep sequencing and imputation, the understanding of the genetic architecture of immune-mediated diseases is becoming a fact, but even more, through the combination of multiple layers of data: epigenome, transcriptome and proteome data, it will become even clearer the delineation of the functional variants modulating disease expression. This will be combined with genome editing technology that will help understand the functionality of the genetic architecture in disease.
Over 30-40% of patients with immune-mediated diseases respond poorly or not at all to their medication. There are several explanations one being the heterogeneity of these diseases where the molecular patterns differ between patients with the same diagnosis. Furthermore, a large group of individuals are never diagnosed and remain “undefined” their entire lives. We develop molecular models that predict response to therapies and molecular pathways that may stratify the diseases not into clinical diagnoses but into molecular diagnoses, and we study in-depth the single cell components that differentiate responders from non-responders.
The work on genetics also involves the understanding of the role of rare variants in disease, the role of the Human Leukocyte Antigen (HLA) system in disease and determination of the polygenic risk score. Furthermore, determination of epigenetic modifications particularly detecting methylated CpG sites which reflect environmental versus genetic influence on gene expression changes in disease. The role of the genotype in determining changes in the microbiota composition is also included in the studies described.
Work is also ongoing on urinary liquid biopsy and the early detection of markers and extracellular vesicles in lupus nephritis. This part of the project is led by the senior scientist in the group, Dr Concepción Marañón.