In many situations experts act adequately, yet without deliberation. Architects e.g, immediately sense opportunities offered by the site of a new project. One could label these manifestations of expert intuition as ‘higher-level’ cognition, but still these experts act unreflectively. The aim of my project is to develop the Skilled Intentionality Framework (SIF), a new conceptual framework for the field of embodied/enactive cognitive science (Chemero, 2009; Thompson, 2007). I argue that affordances - possibilities for action provided by our surroundings - are highly significant in cases of unreflective and reflective ‘higher’ cognition. Skilled Intentionality is skilled coordination with multiple affordances simultaneously. The two central ideas behind this proposal are (a) that episodes of skilled ‘higher’ cognition can be understood as responsiveness to affordances for ‘higher’ cognition and (b) that our surroundings are highly resourceful and contribute to skillful action and cognition in a far more fundamental way than is generally acknowledged. I use embedded philosophical research in a particular practice of architecture to shed new light on the ways in which affordances for ‘higher’ cognition support creative imagination, anticipation, explicit planning and self-reflection. The Skilled Intentionality Framework is groundbreaking in relating findings established at several complementary levels of analysis: philosophy/phenomenology, ecological psychology, affective science and neurodynamics. Empirical findings thought to be exclusively valid for everyday unreflective action can now be used to explain skilled ‘higher’ cognition as well. Moreover, SIF brings both the context and the social back into cognitive science. I will show SIF’s relevance for Friston’s work on the anticipating brain, and apply it in the domain of architecture and public health. SIF will radically widen the scope of the increasingly influential field of embodied cognitive science.

Macrophage transdifferentiation in atherosclerosis: Macrophages are key immune regulators of atherosclerosis. The researcher will study a novel mechanism by which macrophages contribute to disease, via transdifferentiation into myofibroblast-like cells. These transdifferentiated cells acquire characteristics that contribute to atherosclerotic plaque stability, an undescribed feature for macrophages. Applying cell-culture systems, the researcher will identify regulators and mechanisms that contribute to transdifferentiation of macrophages in atherosclerosis.

One of the greatest challenges for modern radiotherapy is ventilation causing motion of tumours and surrounding healthy structures. Technically, modern radiation delivery systems enable in principle very accurate radiation targeting of the tumour and avoiding radiation damage to healthy tissue. However, to deliver sufficient dose to a continuously and irregularly moving tumour, it is necessary to irradiate the tumour with a large margin. Currently such a large margin means irradiating a volume of healthy tissue that is about equal to that of the tumour itself. The healthy tissue damage is itself problematic. But it also prohibits further raising the radiation dose to the tumour to enhance the probability of tumour destruction and thus patient survival. I have invented the use of non-invasive mechanical ventilators to revolutionise radiotherapy delivery, by prolonging breath-hold duration beyond 5 minutes and by reducing and regularising breathing movements. I have demonstrated this works with breast cancer patients. To support its clinical adoption it is now necessary to train other staff to use mechanical ventilation, demonstrate it works with other cancer patient groups, measure the reductions in internal movement of tumours and healthy structures, show how these would produce superior treatment plans and that all this works in another European hospital. My career goal is for me to use the evidence derived from the fellowship to fund the introduction of non-invasive mechanical ventilators first back in our own department (Birmingham, UK), then for me to lead a multi-centre evaluation trial across Europe and finally to lead its introduction into radiotherapy practice throughout Europe.

Pro-inflammatory cytokines play a crucial role in chronic inflammatory diseases. Focusing on spondyloarthritis (SpA), a prevalent and debilitating rheumatic condition characterized by inflammation and abnormal new bone formation, we demonstrated that TNF and IL-23/IL-17 inhibition potently blocks inflammation. However, these treatments have no proven effect on pathologic new bone formation and the resulting structural damage, indicating the unmet need for understanding upstream disease mechanisms. Immune cells, in particular myeloid cells, have been shown to be the major sources of TNF and IL-23 in experimental models. However, we and others failed to demonstrate abnormal cytokine production by myeloid cells in human SpA. What drives these pathogenic cytokines thus remains unknown. We recently found that SpA synovial tissues contain an abnormal stromal population of myofibroblasts, that these myofibroblasts express TNF and IL-23 in vivo and in vitro when exposed to cellular stress, and that stromal expression of these cytokines does not only drive inflammatory responses in vitro but is required and sufficient to induce experimental SpA in vivo. Therefore, we propose that stressed stromal cells can act as primary drivers of cytokine-mediated tissue inflammation and remodelling. Using a translational approach - dynamic sampling of primary human target tissues, functional experiments ex vivo and in vitro, animal models, and targeted interventions in patients – we aim to unravel the role of stromal cells in SpA by defining: 1) the molecular profile of the stromal alterations, 2) the mechanisms of cytokine production by stromal cells, 3) the activation of downstream inflammatory pathways, 4) the role of stromal alterations in tissue remodeling, and 5) the contribution of stromal pathways to experimental and human SpA. Collectively, this project will allow to validate stromal cells as novel therapeutic targets for SpA and related disorders.

The prevalence of the MetS and associated co-morbidities including cardiovascular disease has reached epidemic proportions in the developed and developing world. The cost of treating these conditions represents a substantial part of current European healthcare expenditure, and despite recent advances, treatments for MetS-associated lipid disorders are far from optimal; mainstay lipid-lowering treatments (e.g. statins) reduce cardiovascular risk by only ~30%, and recently-introduced PCSK9 inhibitors are promising, but prohibitively expensive. Moreover, epidemiologic and genetic evidence suggests that these treatment modalities are associated with a significant increase in the risk for development of diabetes. Treatments for other MetS-associated comorbidities, including dyslipidemia, diabetes, obesity, and fatty-liver disease are far from optimal or lacking. In ERC-CoG UNICOM we discovered that genetic inhibition of the E3-ubiquitin ligase IDOL protects mice from the detrimental development of multiple MetS-associated comorbidities. We therefore propose IDOL inhibition as a novel therapeutic strategy to concomitantly target multiple metabolic co-morbidities. However, absence of a high resolution IDOL structure has hampered structure-guided development of inhibitors. In CHANCE, we will capitalize on the high resolution 3D structure of IDOL that we recently obtained. Using this unique structure we aim to identify and validate small-molecule IDOL inhibitors by using a structure-guided development pipeline that combines an established virtual ligand docking protocol, and in vitro and in vivo validation. Lead hits will be used for development of a business and IP strategy to ensure the sustainable development of IDOL inhibitors for treating the MetS.