Obesity is a major public health problem associated with the development of type 2 diabetes (T2D). Leptin targets specific receptors (OB-R) expressed in the hypothalamus to regulate energy balance and glucose homeostasis. Leptin induces decrease of food intake and increase of energy expenditure in normal people but does not function in obese people, indicative of a leptin resistance state. We characterized a new family of OB-R regulators, the endospanin family composed of endospanin 1 and 2 which are ubiquitously expressed. These proteins interact with OB-R and retain OB-R inside the cell limiting the number of OB-R at the cell surface, which can be activated by leptin. Hence, increasing OB-R at the cell surface has been shown to ameliorate leptin sensitivity of the cell. In line with this, endospanin 1 silencing precisely in the hypothalamic Arcuate Nucleus of mouse brain prevents and reverses high fat diet-induced obesity in mice by increasing leptin-induced STAT3 activation. Interestingly, endospanin 1 silencing has differential effects on OB-R signaling pathways: while it increases STAT3 activation it abrogates PI3K/AKT activation indicative of a differential role of endospanin 1 on OB-R function. Moreover, very little is known on the role of endospanin 2 and its effect on OB-R functions. We therefore aim to study i) the differential effect of endospanin 1 and 2 on OB-R signaling, ii) the impact of endospanin 1 general or brain specific knock-out in transgenic mice, and iii) investigate small-molecule compounds, resulting from a High Throughput Screening, and able to increase cell OB-R surface expression and concomitantly signaling. Research on this field would advance the understanding of the function of a receptor important in the field of obesity and help the elaboration of therapeutic tools against obesity and T2D.

The goal of this project is to elucidate the mechanisms responsible for the increase in spontaneous mutagenesis, which is dependent on the Mfd protein in Escherichia coli cells growing without exogenous stressors. Our hypothesis posits that the most of Mfd-dependent mutations arise from the Mfd-mediated exposure of stretches of single-stranded DNA (ssDNA) situated between the elongating RNA polymerase (RNAP) and Mfd. We propose that this occurs after Mfd restarts RNAPs stalled due to obstacles other than DNA lesions, and while it remains connected to the elongating RNAP and the DNA. The rationale behind this hypothesis is that because ssDNA is significantly less chemically stable than double-stranded DNA, it is more susceptible to premutagenic chemical modifications, such as depurination, depyrimidination, deamination and oxidation. Importantly, these modifications are not well-recognized by the NER system, and they do not block the DNA replication process. Identifying the molecular mechanisms that regulate mutation rates carries significant implications for a wide array of scientific fields, including genetics, evolution, medicine, biotechnology, and environmental science. In this context, the contribution of Mfd, an evolutionarily conserved enzyme, to spontaneous mutation rates holds particular significance. This importance stems from the fact that the inactivation of the gene encoding Mfd can be categorized as an "antimutator mutation." In other words, it reduces the rate of mutations, which can be especially relevant in the context of drug resistance and disease prevention.

The adrenal cortex is responsible for the synthesis of steroid hormones. Functional and structural changes occur during aging. The risk of adrenal tumors also increases with age and may be accompanied by alterations in steroid secretion. Animal models show that the senescence of steroid cells is accompanied by recruitment of immune cells, which play a major role in the homeostasis of the adrenal cortex. This balance is disrupted during aging and tumorigenesis. This project aims to study the impact of senescence and inflammation in human adrenal cortex. We will use single-cell transcriptomics/epigenomics and spatial transcriptomics approaches to characterize these mechanisms at the cell level during aging and through different models of tumorigenesis. These approaches will allow to better understand the pathophysiology of adrenal cortex and could lead to the discovery of new targets for treating hormone disorders and tumors.

Cell differentiation progresses via a continuous lineage restriction process where cell potential is reduced as the embryo develops. Pluripotent embryonic cells can beget all somatic cell types, but this capacity is rapidly restricted during the formation of the three germ layers, each giving rise to distinct cell types. Uniquely among vertebrates, a stem cell-like population arising in the embryo rostral part – called cranial neural crest cells (CNCC) – challenges this paradigm. CNCC not only give rise to ectoderm derivatives, such as neurons and glia, but also to cell types canonically associated with the mesoderm such as bone and cartilage of the face. During my postdoctoral training I demonstrated that murine CNCC naturally reverse cell differentiation to return into a pluripotent state during development. In addition, I showed pre-migratory CNCC carry positional information reflective of their spatial origin in the neuroepithelium. However, this identity is subsequently erased with migratory CNCC forming a transcriptionally homogenous population, which later re-diversifies as CNCC undergo commitment events. In my research proposal, using single-cell transcriptomics and genomics assays I seek to uncover and characterize gene regulatory networks and chromatin rearrangements regulating the reemergence of pluripotency programs within CNCC and the underlying reprograming of cellular identity. CNCC represent a unique model to study the molecular mechanisms governing cell-intrinsic behavior but also the role of the niche, which may influence the sequence of events by cell-cell interactions during craniofacial ontogeny. The interdisciplinary scope of experimental strategies included in this proposal will help understand how these fundamental processes are regulated and might result in novel strategies to stimulate craniofacial tissue repair, as cell dedifferentiation and reconfiguration of positional identity are two essential milestones for endogenous regeneration.

Despite significant progress made towards understanding the pathophysiology of Alzheimer’s disease, only few efficient treatments are currently available. Early diagnosis for this disease is also a challenge. This project aims to investigate the phenomenon that are known to occur before the cognitive symptoms, such as the aggregation of pathological proteins (such as tau protein) to develop sensitive biosensors which can be applied to the development of new diagnosis tests and as therapeutic targets of new drugs to stop disease progression.