Irritable bowel syndrome (IBS) is a frequent disorder characterized by visceral pain without established biological markers. The low efficacy of the therapies often leads IBS patients to seek more effective pain killers such as opioids which misuse has becoming a public health problem. In this context, our data showing that enkephalin deficiency in immune cells results in the development of IBS-like symptoms including increased permeability, visceral pain and anxiety, arise the question whether a defect in the opioid tone may define IBS subgroup of patients. The project aims at deciphering the mechanism of this immune-derived opioid-mediated regulation of the intestinal homeostasis and the potential link with the development of patient IBS symptoms. Our project will give opportunities to better characterize IBS patients and/or to develop new therapeutic strategies including new peripheral-restricted opioid drugs to protect patients from centrally-mediated opioid side-effects.

Chronic kidney disease (CKD) affects several millions of individuals worldwide and despite considerable efforts and research, few therapeutic options remain available. The cannabinoid-1 receptor (CB1R) has emerged as potential targets in both metabolic and non-metabolic CKD due to its pro-fibrotic activity. In parallel, the use of SGLT-2 inhibitors appears to be beneficial for CKD patients. We hypothesize that CB1R blockade combined or not with SGLT2 inhibitors would protect kidneys against the progression of CKD and could represent a novel and powerful therapy against CKD. Thus, we want to demonstrate that CB1R inhibition : 1) provides additional benefits to SGLT2 inhibitors in the treatment of diabetic nephropathies and associated renal fibrosis; 2) reduces renal fibrosis and CKD in a model of non-metabolic renal fibrosis; and 3) check whether CB1R expression could be a marker of renal fibrosis in humans and better establish the optimal therapeutic combination in CKD.

Pulmonary fibrosis is a common complication in many acute and chronic respiratory diseases. Among these pathologies, idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease representing the most frequent and severe type of pulmonary fibrosis. IPF is characterized by an irreversible progression toward fatal respiratory failure, therefore, the identification of new therapeutic avenues is the subject of intense international research. Clinical trials implicating anti-inflammatory molecules, such as anti-TNF and prednisone did not show any therapeutic efficacy against IPF. However, new insights on the modulatory role of some immune populations in pulmonary fibrosis, have highlighted the importance of novel strategies that specifically reprogram immune cells instead of deleterious immunosuppressive strategies. Among these modulatory mechanisms, immune checkpoints constitute a group of receptors regulating the intensity of the immune response. Treatments targeting certain immune checkpoints have revolutionized cancer immunotherapy, however, only a few studies have described their role in IPF. The hypothesis underlying this project is that targeting relevant immune checkpoints in IPF would allow the reprogramming of immune cells toward an anti-fibrotic activity. Our preliminary results have identified a novel immune receptor that may play a key role in IPF. We propose here to characterize its expression in IPF patients, to study the ability of this receptor to modulate the fibrotic immune response, and then to investigate its effect on the development of pulmonary fibrosis in transgenic mouse models. Finally, we will assess the therapeutic potential of targeting this receptor in IPF. Successful implementation of interdisciplinary and translational approaches may highlight a new biomarker and a therapeutic immune target in IPF.

Cell plasticity, the ability of cells to change their phenotype, is regulated at transcriptional and epigenetic level and plays a pivotal role in enabling cancer cell to adapt and resist to therapy. By reprogramming their transcriptome and epigenome, tumour cells can adapt to therapeutic pressure by entering a pseudo-dormant “drug-tolerant” state (DTC for “drug-tolerant cells”). Over time, some DTC can acquire genetic and non-genetic resistances, leading to tumour relapse. However, the molecular mechanisms underlying epigenetic-mediated plasticity in adaptive response to treatment are unclear. R-loops, nucleic acid structures consisting of an RNA/DNA hybrid and a single-stranded DNA, are emerging as transcriptional and epigenetic regulators able to participate to cell identity. This research proposal aims to investigate the role of R-loops in driving cell plasticity in response to anticancer therapy, leading to treatment resistance. For this, we will use EGFR tyrosine kinase inhibitors in EGFR-mutated lung cancer cells as a well-established model of adaptive response to therapy. In this context, we will identify the transcriptional and epigenetic changes depending on R-loops, the molecular mechanisms through which R-loops trigger these changes and how they translate into phenotypic plasticity at the single-cell level and genome-wide. Addressing these questions will advance our mechanistic understanding of cell plasticity in adaptive response to anticancer treatments paving the way for the development of therapeutic strategies aimed at preventing disease relapse.

Type 1 diabetes (T1D) results from the destruction of pancreatic islet beta cells by autoimmune CD8+ T cells. We hypothesize that beta cells play a key role in their own autoimmune demise, by increasing their immune visibility and vulnerability. Our analysis of the beta-cell peptidome identified novel antigenic proteins derived from the insulin granules. In particular, secretogranin-5 (SCG5), proconvertase-2 (PCSK2) and urocortin-3 (UCN3) were recognized by human circulating CD8+ T cells and islet-infiltrating CD8+ T cells in the Non-Obese Diabetic (NOD) mouse model of T1D. These T cells are diabetogenic upon in vivo transfer, supporting their pathological role. Two features shared with (pro)insulin may explain this pathogenicity: 1) these granule proteins are released through exocytosis in the bloodstream, thus potentially sensitizing the immune system at distance; 2) they are produced as precursors, and their processing is impaired in T1D, as reflected by increased secretion of unprocessed proinsulin. Our objectives are to investigate: #1. Pathogenicity of SCG5, PCSK2 and UCN3. We will address this: 1A) in the NOD mouse, by characterizing CD8+ T cells reactive to these granule proteins and their pathogenicity in T-cell receptor-retrogenic NOD mice; and 1B) in the human, by using CD8+ T-cell clones/transductants recognizing these antigens, to verify their in vitro capacity to be stimulated by dendritic cells exposed to the ?-cell secretome and to destroy ? cells. #2. SCG5, PCSK2 and UCN3 as novel biomarkers of beta-cell stress and autoimmunity. We will analyze whether these granule proteins: 2A) are increasingly released as pro-proteins (like proinsulin) by beta cells exposed to metabolic or inflammatory stress; and 2B) elicit autoantibody responses in T1D patients. This project will 1) clarify novel pathogenic mechanisms of T1D, i.e. how beta cells may contribute to their own vulnerability; and 2) provide new biomarkers for T1D diagnosis and staging.