Le projet VUE est pré-compétitif. Il a pour objectif la conception et la réalisation d'une nouvelle génération de dispositifs de thérapie par ultrasons focalisés (HIFU) pour le traitement de l'insuffisance veineuse. Les techniques HIFU ont démontré qu'elles représentent une vraie alternative ou un complément efficace aux traitements chirurgicaux conventionnels. Plusieurs innovations sont portées par le projet VUE. La première consiste à mettre au point une nouvelle approche thérapeutique visant à réduire le recours à la chirurgie pour l'application visée. La seconde vise au développement d'une nouvelle sonde ultrasons intégrant un dispositif médical qui rendra possible un traitement faiblement invasif réalisable en médecine de ville. _x000D_ La maladie veineuse superficielle est très fréquente dans la population des pays industrialisés. Même si elle connait un facteur de risque croissant avec l'âge elle concerne aussi une tranche importante de population jeune (15% de 35 ans)._x000D_

This project relates to a method for imaging biological compounds using a non intrusive high resolution surface plasmon resonance microscopy method that we refer to by ``BIOPLASMOSCOPE''. Imaging biological objects in liquid media, from nanoscale to microscale is a key issue of current research in molecular biology. Most approaches developed in the last decades are intrusive, and often require labelling of molecular compounds by fluorescent probes, these probes are not always photostable, and they may also alter the molecular structure of the biological complexes (proteins, DNA, …) they are linked to. The range of scale offered by these fluorescence microscopies is often limited, they are mainly used to detect the presence and/or the colocalization of different molecular elements in cellular media thanks to their fluorescent signature. We propose a different approach. Thanks to our expertise in surface plasmon microscopy, developed both experimentally and theoretically, with the building of an original apparatus called the scanning surface plasmon microscope (SSPM), we propose to extend the ability of this microscope for imaging and detecting nanoscale to microscale objects from visible to infra-red wavelengths. This type of microscopy is completely original, therefore both fundamental and applied research will be necessary. This project is divided in two complementary tasks. On the one side the construction of a commercial prototype, taking advantage of the two laboratory devices that we have built in the past five year. The specifications of this prototype will be elaborated from our discussion with both industrial designers and researchers, to meet both scientific and technical criteria which make this microscope suited for cellular imaging. This prototype will increase our impact in our discussions with industrial companies and will allow us to license our patents more efficiently. On the other side, we will work actively with the valorization structure (ENS Lyon and LST) to expand our list of industrial companies and laboratories (microscopy and surface plasmon) to elaborate a marketing prospection for the development of this technique in the next four years. We will also work with the valorization structure to transfer our expertise, protect our invention, identify and quantify risk elements and promote the originality and attractivity of the BIOPLASMOSCOPE. These two tasks require different skills and ENS Lyon (TTO) and University of Lyon (LST) provide us a very favorable environment. Indeed, this requires a strong interaction in between the scientists, researchers and the persons in charge of the valorization. The fact of all the participants of this project have already worked together in the past four years is a strong advantage and a warranty of the success of this project.

Lung cancer is the main cause of death from cancer with 5-year survival across all stages at 15-20%. About 80% of these tumors are from non–small-cell histological type (NSCLC), including adenocarcinomas, squamous cell, and large cell carcinomas. Surgery is generally accepted as the best treatment option for NSCLC. Unfortunately, only 1/3 of patients with NSCLC are candidates for curative resection. The remaining patients have more advanced stages: multifocal or bulky N2, unresectable IIIB, or metastatic disease. Patients with non-surgical stage III disease are treated with chemo-radiotherapy. The remainder, representing the majority of cases, is treated with chemotherapy or supportive care depending on age, and performance status. Lung cancer remains fatal even with only localized disease at presentation (Stage IA 5 year survival 80%). A 2008 meta-analysis, performed to take into account the new therapeutic regimens, demonstrated a benefit of chemotherapy for advanced NSCLC, improving survival by 9% at 12 months, increasing survival rate to 29% versus 20%. The benefit seen due to the changes in the lung cancer population and drug the regimens used, remained very small. The limited impact of currently available treatments for inoperable NSCLC and the trend towards fewer or no improvement over time should prompt searches for new therapeutic strategies. We discovered a ligand/receptor complex implicated in all steps of cancer progression. Neurotensin (NTS), a 13 amino acid peptide, and its high affinity receptor, NTSR1 lead to cell proliferation, survival, mobility, and invasiveness in specific cancer cell types and facilitates tumor growth and metastasis process. NTSR1 expression level is associated with poor prognosis in patients with ductal breast cancer and head and neck squamous cell carcinomas, and in stage I primary lung adenocarcinoma. NTS-polyplex is a non-viral gene transfer system using NTSR1 endocytosis to facilitate the entrance of the polyplex molecule carrying a plasmid expression vector, into the cell. It was developed to evaluate gene transfer to neuronal cells and neuroblastoma tumors. We demonstrated that intravenous injection of the NTS-polyplex reached and transfected neuroblastoma tumor cells. NTS-polyplex transfection is therefore more efficient in the tumor cells than in healthy cells of organs known to express the NTSR1. The transfection of the thymidine kinase (HSVTK) suicide gene followed by ganciclovir (GCV) treatment decreased the size and weight of neuroblastoma tumors by 30% to 50% and increased apoptosis when compared to controls. These conclusive results call for further development of this approach for lung cancer therapy. In this project, we propose to clarify the contribution of NTS/NTSR1 complex in lung tumor progression, and to identify the NSCLC patients eligible for cancer gene therapy using NTS-polyplex. The evaluation of NTSR1 expression status will be developed on stage IIIB and IV NSCLC patients included in therapeutic protocols. We propose to develop experimental tumors expressing or not NTSR1 and/or NTS to evaluate a possible gene therapy on advanced lung tumor and their metastasis. The Mexican industrial partner, Psicofarma, will be responsible for developing the products for human therapy. The scientific strengths of this project lie with the combination of basic and translational research (French partners), the continued collaboration in experimental research (between the French and Mexican laboratories), and the future biotechnology development (Psicofarma).

Neuropsychiatric disorders frequently are the result of abnormal brain development. Neurons of upper cortical layers particularly contribute to higher cognitive functions. Recent data demonstrate that these neurons arise mainly from intermediate progenitor cells (IPC) in the cortical subventricular zone. The T-box transcription factor Tbr2 is specifically expressed in IPCs and Tbr2 deficiency in humans causes microcephaly and cognitive deficits. Here we exploit this unique expression pattern to study the specification of upper cortical layer neurons.

Learning & memory are fundamental processes allowing encoding, storing, and retrieving information (about space, time and emotion). These processes allow that each individual adapts to the everyday changing environment thereby contributing to species perpetuity. However this ability to “navigate in life” is lost in some individuals. Memory disorders related to aging (such as Alzheimer disease), to stress disorders and to other pathologies (depression, anxiety …) concern a large part of the population, and have a very high human and financial cost. The search for treatments to improve memory is hindered mainly because the biological basis of memory is still unclear. For this reason a better understanding of the mechanisms that underlie memory will allow the development of “memory enhancer” that may treat memory disorders and aid memory in healthy individuals. The discovery that new neurons are created in the adult brain has generated a great interest in the field of learning and memory and of neural plasticity. Indeed, neurogenesis occurs in the dentate gyrus of the hippocampus, which is one of the main brain regions involved in memory processes. For this reason, it has been proposed that adult neurogenesis may constitute a substrate to memory processes and thus, a very promising target for curing or preventing memory disorders. This last decade our knowledge on adult hippocampal neurogenesis has dramatically increased both at a cellular level and at a network level. In contrast, the functional role of neurogenesis remains a hotly debated topic. Over these last years, we have studied the physiological significance of hippocampal neurogenesis and its involvement in pathological memory. We have shown that: 1) adult-born neurons are required for learning and memory, and that an alteration of neurogenesis during senescence or using a transgenic approach lead to spatial memory deficits, 2) reciprocally learning regulates neurogenesis and selects a specific immature neuronal population, the survival of which it increases. This new phenomenon, which is reminiscent of the selective stabilization process occurring during development, is important for learning as its alteration leads to memory impairments in adult or in some senescent individuals. 3) We focused on prenatal stress that constitutes a developmental risk factor for the appearance of memory deficits. We have shown that prenatal stress decreased hippocampal neurogenesis throughout adulthood. Furthermore, these effects are reversible and mediated by changes occurring during the postnatal period. Our project is in line with our previous activities. After demonstrating that adult-born neurons are a key player in learning & memory, we will attempt to understand when and how adult neurogenesis impacts memory. Three lines of research will be developed by studying: 1) the participation of mature adult-born neurons to memory processes, 2) the participation of immature adult-born neurons to memory processes, 3) the implication of neurogenesis in the pathophysiology of memory, using prenatal stress as an experimental paradigm Our expectation is to give a relevant contribution to our knowledge of the neuronal basis of memory. We strongly believe that this field of research has therefore phenomenal potentials to be one of the main axis of research to understand and ultimately improve normal and pathological memory.