Eduardo Villablanca

Perfluoroalkyl substances (PFAS), such as perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluoro hexane sulfonic acid (PFHxS) are a widespread class of man-made persistent, mobile and bioaccumulating pollutants that have been detected in humans, wildlife, and the environment. PFAS are high-risk chemicals causing detrimental health effects and have been linked to many metabolic, developmental, and immunological alterations. Among immunological alterations, PFAS has been associated with intestinal inflammatory diseases and poor responses to COVID-19 vaccination. Our recent FORMAS-supported findings indicate that PFOS disrupts the intestinal barrier function leading to exacerbated inflammation (Diaz et al., DMM, 2021). However, how PFAS affects immune responses that may lead to immune-mediated diseases and poor response to vaccination is yet to be fully understood. Here, using experimental models and systems immunology approaches, we will follow up on our studies to understand the immunotoxic effects of PFAS in intestinal autoimmune diseases and vaccine outcomes. This research will drive novel insights on the role of environmental factors in the etiology of immune-mediated inflammatory diseases and response to vaccines and will provide much-needed knowledge to enable citizens and policymakers to make informed decisions to protect the society at risk of high PFAS exposure.

Harnessing the power of tissue regeneration to promote resolution in chronic autoimmune diseases such as ulcerative colitis (UC) is a promising approach, as mucosal healing predicts sustained remission. However, uncontrolled regeneration may lead to tumor growth, highlighting the need to identify pathways unlinking regeneration and tumorigenesis. My lab has identified liver X receptor (LXR) pathway whose activation promotes intestinal regeneration while inhibiting tumorigenesis in vivo. How LXR unlinks regeneration and tumorigenesis is not known. Using pharmacological tools and genetically engineered mouse models, we will first investigate the mechanisms how LXR activation promotes mucosal healing and inhibits tumor growth. Additionally, we have stratified UC patients into two novel subtypes namely UC1 and UC2. Since the UC1 profile is associated with increased tissue injury and poor response to therapies, we will test whether the stratification into UC1 and UC2 depends on the degree of tissue damage and capacity to heal. Using single-cell transcriptomics, we will generate an atlas of tissue regeneration in UC1 and UC2 patients and test if organoids from UC1 patients display signs of mucosal healing upon LXR activation. We will complement our studies with organoid-immune/stromal co-culture to test the positively identified pathways (eg LXR). This will pave the way towards personalized medicine in UC by identifying novel targets for boosting safer regeneration in UC patients.