Fibrosis in response to tissue damage or persistent inflammation is a pathological hallmark of many chronic degenerative diseases where Idiopathic Pulmonary Fibrosis (IPF) is one of the most severe diseases. IPF is a progressive condition with unknown etiology and a median survival of three years from diagnosis. Current medical treatment is limited to slowing down the disease and thus there is still a high unmet medical need. OGG1 enzyme has a major role in DNA repair in conditions of oxidative stress and also in regulation of gene transcription involved in immune responses. In our ERC grant we developed a first-in class OGG1 inhibitor that protects from exaggerated immune response induced by the proinflammatory mediator TNFα. We have shown with this compound in several airway inflammation models, that inhibition of OGG1 results in a significant down regulation of mediators associated with inflammation and fibrosis, reduced infiltration of immune cells in lungs and increased alveolar integrity compared with control. We have developed a large number of compounds and in this proposal we aim to demonstrate proof of concept (PoC) for the most promising compound in an established model of pulmonary fibrotic diseases in order to select a candidate drug (CD). Our plan is to establish collaboration with industrial partners for further development in order take one compound through preclinical development and clinical phase 1/2a for further commercialization. Treatment with a potent OGG1 inhibitor has the potential to attenuate or resolve the progress of the disease, alone or in combination with existing therapies and increase survival of IPF patients and reduce healthcare costs.

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.

HOMEOTHERMIC SELF builds upon well-established behavioural and neuroimaging methodologies of multisensory integration and recent interoceptive theories to investigate the role of temperature perception in body ownership. The maintenance of optimal body temperature is a survival requirement for all homeothermic mammals, including humans. Temperature has been re-defined as an interoceptive modality, since it provides information about the internal state of the body. Interoceptive signals seem to be integrated with exteroceptive signals from the whole body in the anterior insula to give rise to body awareness, but neuroimaging evidence is still sparse. My first objective is to elucidate the role of visuo-thermal, interoceptive congruency to the sense of body ownership by means of a bodily illusion, i.e. Rubber Hand Illusion, RHI. Next, I aim to investigate the specific contribution of temperature signals to the sense of body ownership by eliciting the RHI using heat lamps, which allow to specifically activate thermal skin receptors. Finally, I will use fMRI to reveal the neural mechanisms responsible for the integration of interoceptive and exteroceptive signals. This project can offer a unique insight into the process that gives rise to a coherent multisensory awareness of the body. As such, it will provide fundamental advance in the fields of body representation, interoception, consciousness and multisensory research. In light of my previous clinical experience, I anticipate that the results might have important implications for neurological and psychiatric conditions characterised by lack of body awareness (e.g. right-hemisphere stroke and eating disorders). My research background in interoception and body awareness combined with the excellent environment of Karolinska Institute, and Prof. Ehrsson expertise in multisensory integration and neuroimaging methods, will provide the perfect synergy to enhance my skills and successfully complete the project.