Epilepsy is a frequent neurological disorder characterized by recurrent seizures resulting from hyperexcitability and hypersynchrony of neuronal networks. Cortical malformations, including Focal Cortical Dysplasia (FCD), are rare sporadic diseases that cause early-life drug-resistant seizures for which surgery is the only therapeutic option to control seizures. Surgical inaccessibility and failures are significant clinical drawbacks. This emphasizes a critical and urgent need for new precision-based therapies for this debilitating childhood disorder. In recent years, my team contributed to revealing that FCD are caused by brain somatic mutations in genes belonging to the mTOR pathway, a signaling cascade regulating key physiological cell functions such as growth, proliferation, and metabolism. During the course of my ERC-funded project, we discovered specific biomarkers in both human and mouse preclinical FCD brain tissues. In EpiSen, we propose an innovative pharmacological strategy based on the selective elimination of mutated cells by repurposing available molecules, that are currently used in clinical trials in other diseases, for FCD-related epilepsy. We hypothesize that abnormal cells, once acutely cleared, will offer a prolonged benefit on seizures. Direct users include applied research groups, pharma companies, the medical community for clinical trials, and patient associations.

The human gut microbiota plays a critical role in safeguarding human health by defending against pathogens and supporting essential metabolic and immune functions. Nevertheless, our understanding of how the gut microbiota influences bacterial invasion and evolution within the human body is incomplete due to the complexity of these interactions. Furthermore, the specific mechanisms through which commensal bacteria, such as Escherichia coli, successfully invade and evolve in distinct human gut microbiota compositions remain unclear. The MICROINVADER project aims to address this knowledge gap, utilizing an established in vitro gut simulator to investigate the precise mechanisms underlying the successful invasion of distinct human gut microbiota ecosystems by the commensal bacterium E. coli. Furthermore, MICROINVADER aims to characterize at the molecular level the processes that shape the evolution of invading strains in response to specific human gut microbiota compositions. Subsequently, MICROINVADER will validate these findings through in vitro and in vivo experiments, focusing on quantifying the selection strength acting on the genetic mechanisms that are crucial for bacterial invasion and colonization in different human gut environments. By unveiling these novel mechanisms driving bacterial invasion and colonization within diverse human gut microbiotas, MICROINVADER seeks to provide critical insights that may have far-reaching implications for enhancing human health. Ultimately, MICROINVADER aims to contribute to our understanding of how to manipulate the gut microbiota in ways that promote and sustain overall well-being.

Defensive behaviours are fundamental for survival. Due to threat diversity, organisms adopt active (e.g. escape) or passive (e.g. freeze) defensive strategies to respond accordingly. The balance between active and passive responses can be defined as "Active-Passive Trade-off" (APT) and disruptions in this process may trigger maladaptive behaviours underlying anxiety and post-traumatic stress conditions, the most common psychiatric disorders in humans. Despite the abundant literature on defensive processes, the mechanisms regulating APT remain unexplained. Building upon the recently discovered role of cannabinoid type-1 (CB1) receptors in fear-coping behaviour, I will elucidate their involvement in the active-passive balance of defensive responses. Herein, we hypothesize that striatal CB1 receptors are critical switches regulating APT, representing key orchestrators of defensive responses. To tackle this, I will i) expose constitutive, cell type and subcellular-specific CB1 mutant mice to ethologically-relevant paradigms designed to assess APT under comparable conditions of innate or acquired threat exposure, ii) dissect how different striatal CB1 subpopulations control APT and iii) characterize underlying CB1-mediated mechanisms, to provide the first evidence of how CB1 receptors regulate different defensive styles. To achieve this, I will combine my expertise in neuropharmacology, behaviour and machine learning with that of the host lab in cannabinoid biology, circuit manipulation and molecular biology. By leveraging cutting-edge behavioural, viral-genetic and bioinformatic tools and expertise from specialists in the field, DefenCB1 will shed light on new mechanisms regulating defensive responses and provide important insights into how striatal CB1 receptors may be implicated in threat response and psychiatric disorders characterized by maladaptive coping. It will also advance my skills and propel my career as an independent researcher in neuropsychopharmacology.

This project will provide proof of concept for the neuroprotective potential of agonists of the mitochondrial protein BRAWNIN. We have identified that BRAWNIN is an important regulator of mitochondrial function in neurons. Mitochondria are essential organelles to support metabolic homeostasis in the cell. Mounting evidence in the literature demonstrate that mitochondria and more broadly metabolic regulation is central to the function of the nervous system. Axons are especially affected by metabolic deregulation, which can lead to axonal degeneration. In this application, we propose that increasing the cellular levels of protein BRAWNIN using a gene-therapy strategy (defined as BRAWNIN agonists) will be protective in neurodegenerative disease, and we will demonstrate this in models of Charcot Marie Tooth disease, a peripheral neuropathy strongly associated with altered metabolism and mitochondria. Overall, our project will provide the first demonstration that BRAWNIN is a target of therapeutic interest in axonal metabolic diseases, which we will further develop with the ultimate goal to develop BRAWNIN agonists for patients.

IgE is a key driver of allergic diseases, which affect approximately one-third of the world’s population. Monoclonal antibodies (mAbs) targeting IgE are approved for the treatment of allergic asthma, and show clinical benefit in a number of other allergic diseases. Yet, a sizable portion of patients do not respond to the drug despite high levels of IgE. There is a clear need to better define which allergy features depend (or not) on IgE, and to find predictive biomarkers in order to identify patients who will benefit from anti-IgE therapy. In addition, use of anti-IgE mAbs is limited by very high cost and the need to perform frequent reinfusion to maintain clinical efficiency. Combining unique mouse models humanized for IgE and its two receptors FceRI and CD23, clinical samples from patients undergoing FDA-approved anti-IgE therapy, and a novel high-throughput IgE repertoire analysis method, the project addresses three key questions: (1) Which IgE features distinguish responders vs. non-responders to anti-IgE therapy, and can it be used as predictive biomarker? (2) Which key allergy features depend on IgE, and through which mechanisms? (3) Can we induce long-term protection against IgE-mediated allergies with a vaccine approach? This translational project will increase our understanding of the basic mechanisms underlying allergic diseases, and has the potential to identify important new therapeutic strategies.