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Tumor genetic mapping has changed the way to cure cancers. Similar revolution is now ongoing in autoimmune diseases, as shown in recent identification of monogenic causes of autoimmunité. Cytokines are essential effectors of immune responses and signal through the JAK-STAT pathway. Inducible su

HYPOTHESIS Multiplexed analysis of the diversity and targets of fungal exposome-induced sensitization enables risk modeling and long-term prediction, at the population and individual levels, of lung function, a correlate of longevity and quality of life. OBJECTIVES Main objective: To establi

Dravet syndrome (DS) is a severe childhood epilepsy caused by haploinsufficiency of SCN1A. SCN1A encodes NaV1.1, the alpha subunit of a type I voltage-gated sodium channel. A significant decrease in NaV1.1 activity generates an imbalance between brain excitation and inhibition that causes DS comorbi

The fight against glioblastoma (GBM) and pancreatic ductal adenocarcinoma (PDAC) urgently requires the development of novel and more efficacious tools to combat these deadly malignancies. This is clearly evidenced by a dismal 5-year survival rate of only 5-10 % for patients suffering from either dis

Involvement of immunity in neurodegenerative disorders is a strongly emerging field, now considered a most promising avenue for the development of innovative treatments and immune biomarkers of clinical interest. Strong evidence support that innate neuroinflammation mediated by microglia and astrocy

Mutations in genes belonging to the RHO GTPase pathway are responsible for intellectual disability (ID), psychiatric disorders and brain development anomalies. The great heterogeneity of phenotypes associated with these gene mutations renders the development of therapeutic strategies strenuous. Stud

Fanconi anemia (FA) is a rare bone marrow failure (BMF) syndrome presenting defects in hematopoietic stem and progenitor cells (HSPCs), anemia, thrombocytopenia and increased risk to progress towards myelodysplasia and acute myeloid leukemia. Even if BMF in FA is thought to be a direct consequenc

Neuromuscular diseases correspond to a vast group of disorders that collectively affect 160 per 100,000 people worldwide. Despite recent progresses, a large proportion of these diseases still do not have definitive treatments. Progresses towards identification of new treatments have been hampered by

Ataxia Telangiectasia (AT) is an incurable inherited disorder arising from bi-allelic mutations in the ATM kinase. Clinically, AT presents as an immune deficiency (ID) with high cancer incidence. ATM has almost thousand predicted targets, which have delayed the identification of cellular mechanisms

We recently identified by investigating a Mendelian psoriasis model a new mutatioon of a gene encoding a protein involved in skin immune responses, which leads to a constitutive activation of the related signaling pathway. By gathering a consortium with high level complementary expertises, we plan n

Among diffuse interstitial lung diseases (ILDs) many pathologies including Idiopathic Pulmonary Fibrosis (IPF) and ILDs related to connective tissues (i.e. rheumatoid arthritis-ILD, systemic sclerosis-ILD) are associated with progressive fibrosis. Beyond them, lung fibrosis is also a complication of

Type 2 diabetes is a major health burden worldwide. The disease is primarily characterized by chronic hyperglycemia and lipoprotein metabolism disorders, reducing both the quality of life and life expectancy, especially by promoting cardiovascular complications. Therefore, patients with type 2 diabe

No treatment for traumatic brain injury (TBI) patients has yet provided prolonged neurorestorative effects. Sustained TBI-induced neuroinflammation (NI) is associated with poor outcomes and a growing body of evidence suggests a link between NI and post-TBI neurodegenerative disorders (ND). Thus, mod

The cornea, transparent tissue protecting the eye, is instrumental to a clear vision. It is composed of a stratified epithelium supported by a mesenchymal stroma. While the stroma is mainly acellular, the epithelium forms the barrier protecting the eye chamber. This epithelial compartment undergoes

Spasticity may develop months after a spinal cord injury with no satisfactory cure. Spasticity mainly manifests by hypertonia and results in part from a hyperexcitability of motoneurons. We showed that calpains (proteases) foster the hyperexcitability of motoneurons by cleaving Na+ channels and KCC2

Preeclampsia is a hypertensive disorder of pregnancy associated with important maternal and perinatal mortality. It complicates 2 to 7% of pregnancies and causes more than 70 000 maternal deaths each year worldwide. Although symptomatic management has improved there is currently no curative treatmen

The potential of immunotherapy to achieve durable responses in some MSI-H colorectal cancers (CRC) has been recognized. However, the need for biomarkers that could predict immune checkpoint inhibitors response became apparent. Beyond MSI-H CRC, the critical challenge is to develop strategies for tar

Stroke is a devastating disease. For ischemic stroke, recent advances with endovascular thrombectomy (EVT) enable revascularization of the occluded artery in a fast and efficient way. Despite this revolutionary intervention and successful recanalization, over half of patients remain disabled. Curren

The CancerProfile multidisciplinary project brings together highly complementary translational research institutes to develop a novel standard of patient stratification for predictive and personalized medicine of pancreatic adenocarcinoma cancer. The overall objective is to fully integrate cutting-e

The PROTECT-Fi project will be conducted in a non-investigated field regarding treatment innovation. The study is based on our original observations: 1/ A key transcription factor, PPARG, that regulates metabolism in renal tubular epithelial cells (TECs) is lost, particularly in mice and pat

FOXP3 expressing regulatory CD4+ T (Treg) cells are instrumental for the maintenance of self-tolerance. Treg cell therapy has a promising potential for the treatment of autoimmune diseases or for the induction of operational tolerance in solid organ transplantation. However human Treg cells are unst

Circulatory shocks (20,000/year in France, 40% mortality) are a major public health issue. Vascular permeability during shocks affects macro and micro-circulation, and correlates independently with mortality in septic and cardiogenic shock. However, determinants of vascular leakage are poorly unders

Hemophilia A and B are inherited bleeding disorders that result in impaired thrombin generation. Correction of bleeding in hemophilia patients is best achieved by the therapeutic administration of factor VIII (FVIII) or factor IX (FIX), the respective missing coagulation factors. Replacement therapy

Esophageal Atresia (EA) is a rare developmental defect of the foregut that presents with or without a Tracheo-Esophageal Fistula (TEF). The prevalence of EA/TEF over time and around the world has been relatively stable (> 165 new EA/year on average in France). EA/TEF is manifested in a broad spectr

A promising path for developing precision medicine in age-related diseases is to take into account the role of disease resistance mechanisms (resilience) in addition to that of disease drivers and risk factors. AD-resilience will accelerate the development of precision medicine for patients that fac

End-stage vital organ failure is a life-threatening condition and the leading cause of premature death worldwide. Economic burden of vital organ failure is currently estimated 25% of total health expenditures, in rapid expansion. Patients with end-stage vital organ failure depend on solid organ tra

Autism spectrum disorder (ASD) as well as other neurodevelopmental disorders (NDD) are a public health priority in France. To help early diagnosis and improve therapeutic care for children, the French government has just set up an early detection program with the creation of «NDD platforms«. Thanks

Although promising, immunotherapies targeting PD-1 are effective in only a fraction of cancer patients and the mechanisms associated with resistance are poorly elucidated. Indeed, tumors use additional pathways to evade CD8 T-cell recognition in particular alterations in peptide transporters TAP. We

Intracranial electrical brain stimulations (EBS) are used during stereoelectroencephalography (SEEG) in pharmacoresistant epilepsy to delineate the epileptogenic zone by triggering seizures and other electrophysiological changes, and to do functional mapping before a surgery that may make patients

Context: Paris region and the French west indies face a specific epidemic of crack-cocaine use, mostly by socially deprived subjects, highly visible in open drug scenes, with little access to the care system. Patients who suffer from crack-cocaine dependence experiment a high rate of medical compl

Periodontal diseases are inflammatory diseases of infectious origin. They are characterized by the destruction of tooth-supporting tissues and lead to tooth loss. The prevalence of periodontitis is high as such disease is found in more than 50% of the population worldwide with more than 10% presenti

Juvenile dermatomyositis (JDM) is a rare and severe idiopathic inflammatory myopathy that begins in childhood. JDM is associated with significant morbidity and mortality and although recent immunomodulating therapies have improved outcome, 40-60% of patients present with relapsing or chronic disease

Ischemic stroke is a major cause of death and morbidity worldwide and therefore an important public health issue. Current treatment, limited to removal of the large vessel occlusion at origin of ischemia, is offered to a minority of patients and not always effective. Novel adjunct therapies are ther

Patients affected by chronic kidney disease (CKD) and on hemodialysis are dramatically affected by cardiovascular mortality, due to vascular calcifications. Some studies suggest that pyrophosphate (PPi) deficiency, a potent calcification inhibitor, could be involved in the development of arterial ca

Cardiovascular diseases cause more than a third of all deaths in Europe. Late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) plays a central role in the management of patients with structural heart diseases by providing high contrast between the injured and healthy myocardium. Unfortuna

Charcot-Marie-Tooth disease (CMT) is a rare and incurable disease of the peripheral nervous system. CMTs are defined according to the cell type affected: either the Schwann Cell (SC) in demyelinating CMT, or motor (MNs) and sensory neurons (SNs) in axonal CMT. More than 100 causative CMT-related gen

In drug-resistant epileptic patients who may benefit from a surgical resection, a poor localization of the epileptic zone (EZ) may lead to neurological sequelae. We have recently developed two new approaches to identify the EZ in a mouse model of focal epilepsy: the first is based on GABA NMR spectr

Retinopathy of prematurity (ROP; ORPHA:90050) remains the major ocular disorder of the neonate and the dominant cause of severe visual impairment in childhood in Europe and North America, but also in middle-income countries. It is a multi-factorial disease of retinal development in which hyperoxia,

COQ8A-ataxia is a rare mitochondrial disorder characterized by slowly progressive cerebellar ataxia, combined with variable features including developmental delay, cognitive impairment, epilepsy, dystonia and myopathic features. This rare ataxia is due to loss of function mutations in COQ8A, with no

Alzheimer's disease (AD) is a neurodegenerative disease remaining incurable yet. AD is a progressive disease with a silent phase for many years before the first symptoms of dementia. Identifying an early biomarker could pave the way for the identification of new therapeutic windows and / or the deve

Monogenic diseases are due to mutations that affect 7,000 different genes. One major roadblock in the diagnosis of rare diseases is the number of gene variants of uncertain significance. Novel methodologies need to be developed specifically to determine the pathogenicity of variants in the coding se

Amyotrophic lateral sclerosis (ALS) and Spinal muscular atrophy (SMA) are rare neurodegenerative diseases characterized by a progressive loss of motor neurons. A marked improvement of SMA patients is observed with recent innovative therapies, but the clinical outcomes are unpredictable and might sho

The repetition of acute kidney injury (AKI) episodes is recognized as a major risk factor for chronic kidney disease (CKD). It is therefore crucial for the long-term quality of life of the patients to limit the incidence of AKI and to improve renal function recovery. Renal replacement therapy (RRT)

Background: Recent investigations have suggested a mucosal origin of rheumatoid arthritis (RA) because of its remarkable association with several mucosal inflammatory conditions. These findings are consistent with the hypothesis of a cross-reaction between auto-immune antibodies directed at both mic

We recently identified a homozygous private mutation targeting the KREMEN2 gene in a multiple consanguineous family with autoinflammatory disease (AID) of unknown aetiology. Two members of the family were strongly affected, in particular a systemic inflammation associated with severe skin manifestat

Kabuki syndrome (KS) is a rare genetic disorder primarily related to mutations of KMT2D (histone-lysine N-methyltransferase 2D), a gene encoding an enzyme which catalyzes the methylation of lysine 4 on histone H3 (H3K4) and regulates gene expression in different biological contexts. KS individuals d

The bioactive vitamin D (1,25D3) is a key regulator of calcium homeostasis. High circulating levels of vitamin D (calcitriosis) lead to hypercalcemia, and are a hallmark of several rare refractory pediatric disorders including idiopathic infantile hypercalcemia type I (IIH1). IIH1 is induced by loss

Neglected tropical diseases caused by vector-born trypanosomatids - African trypanosomiases, Chagas disease and leishmaniases - affect both humans and animals, and disproportionately levy an economic burden on those living in poverty. Progression towards their control or elimination is dependent on

Giant congenital diaphragmatic hernia is a rare congenital malformation with a high morbidity and mortality rate even today despite the fabulous progress of neonatal resuscitation and antenatal follow-up. These advances have made possible to bring increasingly severe forms of hernia to surgery, requ

Hypoxia-ischemia (HI) is one of the leading causes of neurodevelopmental morbidities in infants. There are no pharmacological treatments. HI brain injury is characterized by inflammatory response along with alterations in the blood-brain barrier (BBB), both triggering neuronal damage. INSPIE project

Idiopathic Inflammatory myopathies (IMs) exhibit a strong Interferon (IFN) signature correlated with the disease severity. Although most patients have muscle defects that resist to treatments, myogenesis has been overlooked. Our data show that: a) IM-derived muscle stem cells (MuSCs, which sustain m

The prevention of suicidal behaviors (SB) is a major public health priority worldwide, especially since the phenomenon is feared to worsen in the context of the COVID 19 pandemic. The identification of hig-risk subjects remains a major challenge for clinicians as they currently assess only clinical

Alcoholic hepatitis (AH) is the most severe form of alcohol-associated liver disease (ALD). The pathogenesis of this life-threatening disease is complex and poorly understood due to the lack of animal models, while translational studies suffer from limited access to human liver samples. Despite its

Albinism is a rare disease associating generalized hypopigmentation and severe visual deficits in patients. Currently, the link between altered pigmentation and the retinal development anomalies that lead to impaired vision remain poorly understood. Albinism comprises a group of clinically and genet

Juvenile Idiopathic Arthritis (JIA) is an heterogeneous group of inflammatory arthritis, that cripples pediatric patients, with very little information available on the potential genetic contribution, in pathophysiology and variable responses rates to available therapies. Thus, overall, JIA has very

AL amyloidosis is a rare but devastating disease caused by the tissue/organ deposition of amyloid fibrils composed of a monoclonal immunoglobulin light chain (LC). Despite extensive biochemical studies and clinical investigations, the pathophysiology of this disease is still misunderstood due to the

Annually, Invasive Fungal Infections (IFIs) kill over 1.6 million people globally, a number equal to the mortality due to tuberculosis and greater than the death caused by malaria. Despite the available antifungal drugs, the mortality associated with IFIs remains high due to host-related factors as

Cystic fibrosis (CF) is the most frequent severe recessive disorder in European populations. In France, Staphylococcus aureus (Sa) dominates the lung microbiota of CF children and is able to persist for years in the lung. To date, the exact contribution of Sa to the decline of respiratory function i

Channelopathies induce severe heart rhythm or conduction disorders. Mutations of the KCNH2 gene, that encodes the human (h) ERG channel, is responsible for 30% of all cases of long QT syndrome. Besides, hERG is frequently responsible for off-target effects of several pharmacological agents. With the

Intracranial aneurysms (IAs) affect 3% of the population and IA rupture is a devastating event (40% mortality). The ICAN biobank includes 3400 IA patients with clinical, imaging and DNA. WECAN relies on this exceptional resources for rupture risk stratification among IAs. WP1 uses image processing t

We plan to generate multi-mutant mice carrying up to five heterozygous mutations in different genes involved in sperm production to identify the structural and functional sperm defects induced by these cumulated mutations. We will then compare the mutational burden in genes associated with infertili

The ubiquitin-proteasome system (UPS) is one of the major eukaryotic pathways for intracellular degradation of proteins which are misfolded, oxidized, damaged and/or no longer needed. Denatured proteins to be degraded are specifically tagged with ubiquitin chains before being addressed to the 26S pr

Loiasis is a vector-borne parasitic disease caused by the worm Loa loa and transmitted from human to human through the bites of Chrysops. This disease is a public health concern for about 20 million people living in forested areas of central Africa. In 2016, we demonstrated that high grade infection

Total hip replacement (THR) surgery is the second most common surgery in France with a total number of around 150,000 patients per year. However, there remain risks of failure which may have dramatic consequences and which depend on the implant primary stability. An increasing number of THR is perfo

Pain in Parkinson’s disease (PD) is one of the non-motor symptoms contributing to impaired quality of life of patients. Among the different types of pain observed in PD, central pain has the highest severityand appears to be more difficult to treat than the nociceptive pain. A better knowledge of th

Liver transplantation is the only therapeutic option for patients with end-stage liver disease. However, the rising prevalence of chronic liver diseases, such as non-alcoholic fatty liver disease (NAFLD), has increased the number of patients requiring liver transplantation, and the duration on waiti

Fallot's tetralogy is the most common cyanotic heart malformation in newborns. It can be corrected by surgical management which consists in enlarging the right ventricular outflow tract. This approach generates pulmonary valve leakage that must be repair. Synthetic or chemically-treated biological p