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Pathophysiologic role of HDAC6 overexpression consecutive to a mutation abrogating a miRNA-mediated post-transcriptional regulation in a X-linked chondrodysplasia. – CHONDRO-X
We work on a new form of familial X-linked dominant chondrodysplasia (Chassaing et al, 2005). The phenotype in males is lethal and associates platyspondyly, rhizomelic shortening of the members, specific brachydactyly, hydrocephaly, facial dysmorphism and microphthalmia. The phenotype in heterozygou
PAthogenesis of Sjögren’s Syndrome and of AutoImmunity-associated Lymphomas – PASSAIL
Autoimmune diseases (AID), which affect more than 5% of the population, result from the interaction between genetic and environmental factors, and involve innate and adaptive immunity. An increased risk of lymphoma is observed in the 3 main systemic autoimmune diseases, rheumatoid arthritis, systemi
Genomic alteration of conserved non coding sequences in human malformation – EvoDevoMut
One of the key discoveries of vertebrate genome sequencing projects has been the identification of highly conserved non-coding sequences (CNCs) and their great amount (3% of the human genome according to the ENCODE project). In particular, key developmental genes located in gene deserts are particul
T lymphocytes releasing enkephalins in the gut : how to modulate chronic inflammatory pain – LYMPHOPIOID
Pain is clearly the number one reason for patients to consult medical doctors, and is the first symptom they want to be relieved by therapy. Opioids are the most efficient drugs to treat pain but their chronic use at pharmacological doses results in major side effects. The observation that analgesia
Search for erythroid regulators involved in iron homeostasis – ERYFER
Erythropoiesis is the process by which the hematopoietic tissue of the bone marrow produces red blood cells (erythrocytes). The principal function of erythrocytes is to deliver oxygen from the lungs to the other tissues of the body. To perform their duty as oxygen carriers, erythrocytes require iron
Pathophysiological mechanisms of androgen and glucocorticoid receptors in skeletal muscle, and identification of new drug targets for prevention and treatment of muscle atrophy. – Androgluco
Skeletal muscle is a dynamic tissue that has the capacity to regulate its size and function in response to a variety of external clues. Muscle inactivity, fasting, diseases (e.g. AIDS, cancers, septic shocks, diabetes) and ageing induce muscle atrophy and weakness. Sarcopenia is also a common sign o
Stem cells and cell therapy for sensori-neural deafness – Stem Cells and Hearing Loss
Sensori-neural hearing loss (SNHL) represents a major public health problem and the most common sensory deficit in humans, affecting 1 in 1000 newborns and a significant portion of the elderly population. In most cases, SNHL is associated with a permanent loss of auditory hair cells (HCs) within the
Role of alternative macrophage in human atherosclerosis and functions of the nuclear receptor PPARg – AlMHA
- - - - Monocytes / macrophages are central cells in the development of metabolic disorders and associated diseases such as atherosclerosis, because they can infiltrate the arterial wall, accumulate lipids (namely cholesterol) and contribute to the maintenance of a local inflammatory and pro-thrombo
Mechanisms of conversion of human white to brown adipocytes – miRBAT
The increase in the frequency of overweight/obese people has reached a qualified epidemic stage with more than one billion overweight (IMC > 25 kg/m2) and at least 300 millions clinically obese (BMI > 30 kg/m2) with tremendous costs for health care systems. A positive energy balance, which is acco
Phosphorylation/O-GlcNAc interplay in heart failure: pathophysiological roles and interest as biomarkers – PHOGIHF
Heart Failure (HF), especially secondary to myocardial infarction, still represents a major health concern worldwide. Improvement of HF treatment requires both to improve our knowledge on the molecular mechanisms of the disease and to development relevant biomarkers that may predict the outcome. Fol
Genetics of cortical dysgenesis (CD) and pathophysiology of Tubulin-related forms (TrCD) – GenCo-TrCD
Cortical dysgenesis (CD) associated with gyral abnormalities, such as lissencephaly, pachygyria and the polymicrogyria (PMG), whose prevalence is estimated at about 1%, represent major causes of severe forms of mental and epilepsy. Genetic studies have shown the involvement of many genes in diverse
Expression and function of Gllut transporters in the expansion and differentiation of hematopoietic stem cells towards distinct lineage fates – GLUTStem
Extensive research has been undertaken to elucidate the roles of cytokines in the proliferation and differentiation of hematopoietic stem cells. However, the importance of metabolism in these processes has only been cursorily assessed. During the past few years, our group has begun to approach this
Molecular and cellular mechanisms of Meckel/Joubert ciliopathy – FOETOCILPATH
Meckel syndrome (MKS) is a severe autosomal recessive ciliopathy, which is often lethal prenatally or at birth, characterized by pleiotropic phenotypes such as multicystic kidney and hepatic duct dysplasia, occipital meningo-encephalocele and posterior fossa abnormalities (including cerebellar vermi
Early abnormalities in a mouse model for myotonic dystrophy : a model for Congenital Myotonic Dystrophy ? – MODELCDM
Myotonic dystrophy type I (DM1) is a dominantly inherited disorder with an incidence of 1 in 8000 adults. Clinically, it is highly variable. The adult onset form typically presents distal muscle weakness, myotonia, presenile cataracts, cardio-respiratory problems, hypersomnia, hyperinsulinism, behav
Role of Stat3/Sosc3 SIgnalling in Modulating the Pathogenesis of Atherosclerosis and vascular Aneurysm – SIMPA
SOCS proteins have emerged as key physiological regulators of both innate and adaptive immunity and control the development of various immuno-inflammatory diseases. SOCS3 is expressed in atherosclerotic lesions and the current paradigm suggests an athero-protective role through inhibition of STAT3 s
Simulation, Analysis and Measurements of Obstruction in Respiratory Airways – SAMOVAR
The submitted project is truly multidisciplinary by gathering teams of physicists, mathematicians, researchers from biomedical engineering and medical doctors towards an ambitious goal: to understand in detail the relationship between the local mechanical properties of the tracheobronchial tree and
Neonatal Fc receptor-mediated tolerance induction in alloimmune and autoimmune conditions – Immunotolerins
Several pathological situations result from a break in immunological tolerance towards endogenous molecules, as seen in autoimmune diseases, or from the inability to mount tolerance towards exogenously administered molecules, as observed in alloimmune responses to protein therapeutics. In this proje
Role of a MAP3 kinase in peripheral insulin resistance and pancreatic beta-cells failure in Type 2 diabetes – TPLIRBCELL
Functional and genetic crosstalks linking Wnt signalling to energy balance in the liver – WNT-METABOLIV
The liver plays a key role in metabolic homeostasis, as it can either store excess energy or provide nutriments for the other organs following the nutritional state. Liver anabolic and catabolic functions are realized in different regions of the lobule, along a porto-central gradient defining the li
-Genetic Diversity and Phenotypic Monotony in non-atherothrombotic arterial pathologies - 2 – GDPM-2
The etiologic diversity of TAAD, our ability to have access to human clinical cohorts and DNA collections, to diseased as well as normal human aortic tissues, and to obtain primary cultures of aortic cells, provide us with a unique opportunity to progress further in the pathology of these frequent a
CXCL12 and tissue regeneration: Mechanisms of action and therapeutic potential – chemrepair
The chemokine CXCL12 is unique among chemokines by the pleiotropic roles that it plays in embryo and adult life. The exceptional conservation of CXCL12 structure & function in mammalians announces the essential roles played by this singular chemokine. To this regard the contribution of CXCL12/CXCR4
Genetic determinism and functional and pharmacological evaluation of spinocerebellar degenerative disorders linked to lipid gene mutations. – LIGENAX
Hereditary spastic paraplegia (HSP) and cerebellar ataxias (CA) are rare diseases of the central nervous system often referred to as spinocerebellar degenerations because of the great clinical overlap that exist between these diseases. HSP is characterized by gradual spasticity and weakness of the l
Epigenetic, Genetic and Fetal Growth (EPIFEGRO) – EPIFEGRO
Fetal development as well as cellular fate requires strict coordination between genetic and epigenetic programs. Abnormalities of one of them can affect permanently the future individual. One hallmark of epigenetic modification is genomic imprinting. Loss of imprinting (LOI) through loss (LOM) or ga
Role of Anks6 and its partners in kidney cystic disease – renalcyst
Polycystic Kidney Disease (PKD) is the most common genetic disease that leads to kidney failure in humans. Two genes, PKD1 and PKD2 account for the vast majority of cases of ADPKD. Although potential therapies are been tested in clinical trials, no prevention or causal treatment exists at the presen
Diamond-Blackfan Anemia, a paradigm for ribosomal diseases – RiboCrash
A number of rare genetic diseases have been recently linked to mutations in genes encoding proteins involved in ribosome biogenesis or ribosome function. Most of these pathologies correspond to inherited bone marrow failure syndromes. These recent findings have led to the new concept of ribosomal di
Environmental, Genetic and Epigenetic factors predisposing to common male urogentital malformations – HYPOCRYPT-ENVIROGENEPIG
Hypospadias (H) and cryptorchidism (C) are the most frequent congenital malformations, 1/300 and 3-6/100 in male newborns. In less than 5% of cases, H and C reveal a well characterized endocrine genetic disease. But in the vast majority of well-cases (> 95%) H and C remain without explanation. These
Renal Mechanisms of Chloride-Dependent Hypertension – HYPERCLO
The molecular mechanisms underlying the pathogenesis of hypertension are still poorly understood. What is known is that excessive dietary salt represents a major risk factor for human hypertension, and it is clear that hypertension results from increased sodium absorption within the distal nephron o
Role of Notch3/RBP-JK on renal, cardiac and brain function under basal conditions and during hypertension – HyperNotch3
Control of local, peripheral hemodynamics has major clinical implications in a variety of conditions and diseases in which myogenic tone and autoregulation are key components, such as hypertension, stroke, chronic kidney disease, heart failure, vascular dementia and atherosclerosis. The general o
Role of PiT1 in Liver Regeneration, Inflammation and Carcinogenesis – PiT-LIRIC
The aim of this project is to assess the role of PiT1 in liver regeneration, inflammation and carcinogenesis. PiT1 ‘SLC20A1) is a widely distributed membrane protein with multiple functions: it is a sodium-phosphate cotransporter, a receptor for gamma retroviruses, and, as recently demonstrated b
Neuropilin as new co-receptor of leptin – NRPLEP
Neuropilin-1 (NRP1) is a pleiotropic membrane receptor involved in axon guidance in the central nervous system and in angiogenesis by interacting with specific co-receptors such as plexins or VEGF receptors. NRP1 has also been reported to be involved in the regulation of hematopoiesis and in cancer
Therapeutic of hepatic metabolic disorders: AMPK activation and control of hepatocyte ploidy – AMPLOI
Excessive hepatic lipid accumulation resulting from insulin resistance is the first step in the pathogenesis of hepatic steatosis. It is critical that a balance between hepatic lipid synthesis and oxidation is maintained to prevent lipotoxicity. The energy sensor AMPK regulates fatty acids partition
Implication and rescue of Tau mis-splicing in myotonique dystrophy – NEUROSPLICEDETAU
Myotonic dystrophy type I (DM1) is a rare inherited neuromuscular disease affecting multiple organs. The genetic mutation is located on chromosome 19 and consists of dynamic expansion of a trinucleotide motif (CTG) in the 3’ untranslated region of DM protein kinase gene (DMPK). The aetiology of DM1
Dynamics of STIM/Orai/TRPC interaction in the normal, hypertrophied and failing cardiac myocyte – Cardiosoc
Ca2+ homeostasis is clearly altered in cardiac hypertrophy and heart failure and new therapeutic approaches for heart failure based on sarcoplasmic reticulum (SR) Ca2+ cycling are under development including viral-based SERCA2a (sarco/endoplasmic reticulum Ca2+ ATPase type 2a) gene transfer. Recentl
ROLE OF TYPE 4 PHOSPHODIESTERASES IN CARDIAC PATHOPHYSIOLOGY – PDE4HEART
Cardiac hypertrophy is an adaptive mechanism that often leads to heart failure and sudden death. Heart failure is a major health problem representing about 2% of health costs in developed countries and this trend is predicted to increase. Chronic activation of the beta-adrenergic receptor (beta-AR)/
Genetics and Physiology of the heartbeat generation – Beat-Genesis
Heart automaticity is a fundamental physiological function in animals. In the adult heart of higher vertebrates, automaticity is generated in the sino-atrial node by specialized “pacemaker” cells having low contractility and generating a periodic electrical oscillation. The readout of cardiac autom