Type 2 diabetes (T2D) is a multifactorial disease affecting over 450 million people in Europe alone, amounting to the burden of life-threatening diseases and worsening quality of life. Skeletal muscle is affected early in T2D and contributes to the fast decline of whole-body glucose homeostasis, which is called insulin resistance. Interestingly, even when isolated from the body and cultured in a laboratory in non-diabetogenic conditions, the skeletal muscle cells do not lose the characteristics of the donor, i.e., the cells remain insulin resistant, indicating the existence of a cell-autonomous mechanism that retains the metabolic memory across generations of cells. Nonetheless, such a mechanism remains elusive. Accumulating evidence suggests a potential role of histone post-translational modifications as essential vectors of inheritable information, but it is still a matter of intense debate. In this project, to address this question and understand the pathology of T2D, we will trace a comprehensive genome-wide map of histone post-translational modifications induced by T2D in human primary skeletal muscle cells and investigate whether these histone marks can store and transmit information about the metabolic phenotype from the donor to the next generation of cells. Targeted studies using pharmacological and genetic interventions will then address the role of histone modifying enzymes in metabolic memory transmission. The outcomes could lead to a novel understanding of a broader system of cellular memory storage and transmission. By characterizing the disturbances caused by diabetes in the epigenome using state-of-the-art techniques and multidisciplinary approaches, we could pave the way for innovative clinical interventions addressing a critical global health challenge.

Pancreatic islet transplantation is essential for diabetes treatment. Outcome varies due to transplantation site, quality of islets and the fact that transplanted islets are affected by the same challenges as in situ islets. Tailor-making islets for transplantation by tissue engineering combined with a more favorable transplantation site that allows for both monitoring and local modulation of islet cells is thus instrumental. We have established the anterior chamber of the eye (ACE) as a favorable environment for long term survival of islet grafts and the cornea as a natural body window for non-invasive, longitudinal optical monitoring of islet function. ACE engrafted islets are able to maintain blood glucose homeostasis in diabetic animals. In addition to studies in non-human primates we are performing human clinical trials, the first patient already being transplanted. Tissue engineering of native islets is technically difficult. We will therefore apply genetically engineered islet organoids. This allows us to generate i) standardized material optimized for transplantation, function and survival, as well as ii) islet organoids suitable for monitoring (sensor islet organoids) and treating (metabolic islet organoids) insulin-dependent diabetes. We hypothesize that genetically engineered islet organoids transplanted to the ACE are superior to native pancreatic islets to monitor and treat insulin-dependent diabetes. Our overall aim is to create a platform allowing monitoring and treatment of insulin-dependent diabetes in mice that can be transferred to large animals for validation. The objective is to combine tissue engineering of islet cell organoids, transplantation to the ACE, synthetic biology, local pharmacological treatment strategies and the development of novel micro electronic/micro optical readout systems for islet cells. This regenerative medicine approach will follow our clinical trial programs and be transferred into the clinic to combat diabetes.

Emotions guide humans and animals in the selection of behavioral strategies to optimize outcomes and promote well-being. Repeated or unexpected strong negative stimuli such as stressors impair the processing of emotions and lead to the development of mood disorders such as depression and anxiety. Understanding how individuals control their emotions and cope with stressful events has become a major clinical challenge for the development of new treatments. This project aims to define the circuit mechanisms that control emotional regulation. I will focus on a brain region key in emotional regulation, namely the lateral habenula (LHb). Over the past decades, clinical and preclinical studies have identified the LHb as a major hub in the regulation of negative emotions and in the induction of mood disorders. Recent studies have highlighted that lateral hypothalamic (LHA) excitatory inputs to the LHb drive negative emotions (i.e., aversion) and may play a role in depression. However, how the LHb integrates diverse types of inputs to promote negative emotions remains unknown. The main hypothesis of the project is that the complex regulation of emotions is defined by a discrete organization of inputs to LHb that underlies maladaptive circuit-specific dysfunction in models of stress. I will investigate here the molecular and functional properties of the LHb neurons based on their discrete inputs from the LHA. I will use a multidisciplinary approach combining cutting-edge spatial transcriptomics, neuronal tracing and optogenetics to define for the first time the role of the molecularly-defined discrete LHA-LHb pathways in normal and disease-related behaviours. This project will provide key insights about the regulation of mood by the lateral habenula and how the inputs from the lateral hypothalamus are key in the pathophysiology of depression and anxiety disorders.