Chronic Obstructive Pulmonary Disease (COPD) is a common respiratory disease mainly linked to prolonged tobacco use, with no curative treatment to date. It is often associated with emphysema, corresponding to destruction of the lung alveoli, which pathophysiology remains poorly understood. In this project, we aim at building a standardized 4D in vitro model of pulmonary alveoli (alveolospheres), by controlling the mechanical and chemical constraints governing cellular organization in vivo. We will use photopolymerized hydrogel microwells, thanks to a collaboration established for 2 years with the ALVEOLE© company, to seed alveolar epithelial cells (AEC) and human pulmonary mesenchymal cells and observe self-organization into spheroids. We will then expose cells to a cyclic mechanical stretch mimicking human breathing in order to observe the consequences on alveolospheres functionality. In addition, we will create a model of emphysema using several approaches. First, we will vary the size and stiffness of the microwells in order to mimic the mechanical stresses of emphysema. We will also expose the alveolospheres to cigarette smoke extract, thus reproducing the chemical aggression mainly involved in emphysema. By combining these approaches, we will be able to determine the role of the environment in the disease’s development. Finally, the respective role of each cell will be evaluated by performing heterologous cultures combining AECs from patients with emphysema and mesenchymal cells from patients without emphysema and vice versa. The pathophysiological pathways of emphysema will be evaluated for each condition: protease / anti-protease balance, apoptosis, senescence, inflammation. While controlling physical, chemical and biological parameters in our organoid culture, associated with dynamic stretching, we will obtain an innovative 4D pulmonary organoid model which can be used both in physiology and pathology.

Brain stimulation or neuromodulation is a promising therapeutic tool for the treatment of many neuro-psychiatric conditions (epilepsy, chronic pain, stroke, depression, etc.). Its success is currently limited by its invasiveness and its lack of precision. Indeed, current stimulation approaches reach entire areas of the brain without specificity for neural networks. Non-invasive stimulation targeting specific brain circuits is therefore a major scientific and medical issue. This project aims to combine 3 cutting-edge techniques to design a technology for the non-invasive neuromodulation of targeted neural networks and mechanisms. We will develop an innovative toolbox system, combining synthetic chemistry for the development of fluorescent organic nanoparticles, optogenetics and a brain-machine interface for real-time stimulation. Fluorescent organic nanoparticles will convert extracerebral infrared light waves into visible light capable of activating neural circuits that selectively express an opsin. Closed-loop stimulation, as a function of real time brain activity, will add to the targeting of neural circuits, that of their specific mechanisms. Precision non-invasive neuromodulation and the synthesis of organic compounds for infrared-to-visible photo-conversion are areas of cutting-edge research. Based on clear and convincing preliminary results, we are proposing a research project to initiate the resolution of these two scientific challenges. Our results will strongly contribute to the development of disruptive technology for chemical and biological sciences as well as medicine.

Fear and anxiety-related disorders such as post-traumatic stress disorder (PTSD) are among the most frequent psychiatric conditions and represent a major public health concern. Such disorders are commonly viewed as impairment of fear memory, its consolidation in particular. Pavlovian fear conditioning in mice models one key aspect of panic attacks and PSTD: the spontaneous recall of fear memory. To date, the circuits and mechanisms responsible for fear memory consolidation remain unknown. From our preliminary data and a large body of literature, the present project proposes to study the ventral hippocampus - prefrontal cortex network as the core circuit for fear memory consolidation. To this end, we will combine state of the art behaviour, electrophysiology and optogenetic techniques to thoroughly dissect and manipulate this circuit and its mechanisms. Beyond physiology, interfering with fear memory circuit mechanisms would be a novel and promising therapeutic strategy.

Fragile X syndrome is the most common inherited form of intellectual disability and a monogenic cause of autism. This neurodevelopmental disorder results from mutations in the FMR1 gene leading to the lack of expression or abnormal function of the FMRP protein. We demonstrated that FMRP is regulated by the post-translational modification sumoylation, which is essential to its function. Our goal here is to understand how the recurrent Fragile X R138Q mutation, which is close to the SUMO active site of FMRP, affects its regulation. We will use our Knock-in R138Q-FMRP mouse model in which we show alterations in FMRP sumoylation, in AMPAR targeting/trafficking and spine density leading to plasticity defects and altered socio-cognitive behaviours. The aim here is to assess two drugs already used in clinics to correct the molecular, cellular, physiological and abnormal behaviours that are characteristic of the disease.