Microbes have remarkable capabilities to attach to surfaces of natural and artificial systems, eventually leading to the formation of biofilms and associated chronic and persistent infections. It is extremely appealing to understand how bacteria interact with three- dimensional surface topographies and how to design smart patterns as a strategy to create antifouling and biocidal materials. Here I propose a dynamic strategy, merging verstile and large-scale surface modification teqhniques based on mechanical wrinkling of soft bilayers, that I developed at Imperial College London, microfluidics and microbiology. The goal of MOBILE is investigating the mechanical confinement exerted by non-planar surface curvatures and spatial heterogeneities induced by fluid shear on bacterial initial attachment and removal, in confined environments. Specifically (Aim 1), I will evaluate the combined action of surface topography and fluid shear over bacterial proliferation, motitly and viability, incorporating nano- to micro-scaled wrinkled geometries in microfluidic channels, mimicking biological tissues surfaces and implantable medical devices, testing a series of different clinically relevant bacterial strains (such as Enterococcus faecalis, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae). I will also (Aim 2) develop antifouling and removal strategies by investigating the mechanical response of adhered bacteria, using patterned surfaces as stimuli-responsive probes "actuated" by means of mechanical deformation (i.e., by extension and compression of the wrinkled topographies) to induce detachment and surface cleaning under fluid dynamic conditions. Overall, I aim to elucidate new methodologies for bacterial removal at different stages of biofilm formation paving the way towards the development of new classes of biomedical devices and to contribute to an important step in direction of controlling implant-associated infections.

Heart failure (HF), the ultimate outcome of many cardiovascular pathologies, imposes a significant global health and economic burden while remaining associated with high mortality rates. There is therefore an urgent need for innovative approaches to comprehensively understand and treat HF. Most HF research, has thus far focused on the pathophysiology of the heart, only partially covering the role of non-cardiac organs, despite HF being a complex multiorgan syndrome. The extent to which extra-cardiac organs, particularly those playing a key role in metabolism control, contribute to HF remains largely unknown. CODE-HEART aims to bridge this knowledge gap by focusing on metabolic interorgan mechanisms of disease. Our metabolism is temporally coordinated across tissues by the circadian clock system, which orchestrates myriad of physiological and metabolic processes. My recent work has highlighted the significance of peripheral tissue-tissue communication for daily metabolic homeostasis. Notably, my preliminary findings suggest that when the heart is under stress, systemic glucose and lipid diurnal metabolism is rewired. In this project, I will test the hypothesis that the failing heart can alter systemic diurnal metabolic rhythms via the release of specific cardiac-secreted factors. To do so, I will first determine the impact of HF on systemic metabolic rhythms and on the diurnal transcriptional landscape of liver, skeletal muscle and white adipose tissue. Using specific knockout animal models, I will investigate the consequences of systemic metabolic rewiring on cardiac function in HF. Finally, I will pinpoint the metabolic communication network between the heart, liver, and other metabolic tissues by labelling cardiomyocyte-specific secreted proteins and screening their functions in vitro and in vivo. In summary, CODE-HEART will significantly advance our understanding of the metabolic and molecular adaptation occurring in HF.

Inflammatory bowel disease (IBD) defines a group of chronic inflammatory disorders of the digestive tract, with ulcerative colitis and Crohn’s disease being its two major clinical manifestations, affecting 2.5 million people in Europe. The high prevalence of IBD in Europe and the multiple clinical challenges associated with a significant degree of unresponsiveness to anti-inflammatory therapies and development of complications requiring surgical intervention demand a deeper understanding of the cellular and molecular mechanisms underpinning IBD. This project aims to understand the role of the process termed Epithelial–to–Mesenchymal Transition (EMT), an embryonic cellular trans-differentiation program re-launched in many pathological conditions, in the pathogenesis of IBD. EMT has in fact been detected in the inflamed intestinal mucosa and surrounding fibrotic areas of IBD patients and experimental models of colitis, however whether EMT functionally contributes to the pathogenesis of IBD is poorly understood. The INFLEMT project aims to: 1) profile EMT in human IBD to identify its cellular features and correlation with the disease stage; 2) elucidate the impact of EMT on the integrity, functionality and regenerative capacity of the intestinal epithelial barrier; 3) explore the effects of EMT on fibrosis development and modulation of the immune response to assess its role in sustaining the chronic intestinal disease. These objectives will be pursued by utilizing patient-derived biopsies as well as novel mouse models to manipulate EMT in the intestinal epithelium. Comprehensive analysis, including RNA-sequencing and multispectral imaging, of the involved cellular and microenvironmental components (epithelial barrier, immune cells, fibroblasts) will be performed in acute and chronic colitis settings to mechanistically configure EMT as an epithelial injury response and a major functional driver in the pathogenesis of IBD.

Mural cells (pericytes and vascular smooth muscle) enclose blood vessels and are critical for vascular homeostasis. Absence or malfunction of pericytes or vascular smooth muscle results in aneurysm formation in small or large blood vessels, respectively. Our previous work showed Tbx18 is selectively expressed in mural cells of multiple adult organs. Preliminary data indicates that, in mice, ablation of Tbx18 in mural cells results in aortic tortuosity and lethality due to rupture. These observations led to the hypothesis that transcriptional regulation by TBX18 in mural cells is critical for the development of functional vascular networks. To fully understand the roles of TBX18 in mural cells and eventually place it as a gene involved in human vascular disease, we propose to: 1) fully characterize the vascular phenotypes of Pdgfrb- Cre;Tbx18 mutants; 2) identify genes directly regulated by Tbx18 in mural cells; and 3) test a putative involvement of TBX18 in human aneurysmal diseases.

Organismal responses to environmental threats involve the activation of both resident and monocyte-derived macrophages, key components of the innate immune system. Macrophages are capable of rapidly sensing micro-environmental changes and of reacting with distinct activities ranging from specialised homeostatic functions, to the activation of effector functions in tissue immune surveillance. These diverse biological outcomes are brought about by the coordinated rewiring of both metabolic and transcriptional networks. Although much is known about the metabolic configuration and the transcriptional signatures of activated macrophages, their reciprocal influences have not been systematically investigated. Metabolic changes linked to acute activation are primarily, although not exclusively, driven by transcriptional changes; nevertheless, how these changes are coordinated and implemented over time remains unsolved. In addition, changes in metabolic state are accompanied by changes in metabolites availability, some of which are cofactors or co-substrates of chromatin-modifying enzymes, essential players in the control of gene expression. I aim to unravel key mechanistic principles on the interplay between transcriptional and metabolic control in macrophages by adopting two complementary approaches: (1) I will identify the complement of transcription factors controlling dynamic metabolic changes at different times during macrophage activation by combining genomic and metabolomic techniques; (2) I will characterise how metabolic pathways signal to specific enhancers thus eventually affecting inflammatory gene transcription and chromatin changes. This project will contribute to systematically dissect fundamental principles of integrated cell control in response to micro-environmental stimuli, advancing our understanding of the coordination between metabolic re-programming and gene transcriptional programs.