Through the proposed collaboration, we intend to join forces and take advantage of expertise in distinct domains to further characterize the link between attention and statistical learning at the individual level, as well as to shed light on the mechanisms by which the nfluence of topdown attention might come about. The impact of other cognitive abilities (fluid intelligence, working memory) as well as of motivational and emotional factors will be taken into consideration.

To this end, we will:
1- Investigate the determinants of inter-individual behavioral variability in statistical learning, particularly in relation to inter-individual variability in various forms of attention.
2. Take advantage of an expert population (action video gamers) presenting enhanced attention to test the impact of augmented attention on statistical learning, aiming at confirming and extending the preliminary observation of faster learning in gamers.
3. Gain a better understanding of the neural structures recruited as statistical learning unfolds – with a special interest in attentional regions.
4- Strengthening contacts and exchange between the two partners – through regular remote (online) meetings throughout the duration of the grant, and via the joint organization of a two-day workshop gathering researchers from the University of Geneva, Princeton University and international world-known researchers on learning.
5- Offering seminars and developing teaching resources, both about the basic science of attention and learning, and about how to translate these insights into education.
6- Offering week-long residencies for PhD/post-doc students in the two laboratories, in support of the scientific goals of the project.
7- Potentially following-up the proposed projects with further jointly funded applications.

Western society enjoys almost unrestricted access to food, but the combination with low levels of physical exercise results in a condition termed the metabolic syndrome (Grundy et al., 2006). Typical features associated with this syndrome are an increase in diabetic patients as well as a high risk for cardiovascular complications and enhanced potential for developing cancers. Although many research proposals are currently addressing the impact of metabolic changes caused by an excess availability of sugar and fat in our diet on the survival and proliferation of cells in our tissues, almost none of these studies is asking the question how tissues and their functional properties are changing under such conditions.

In order to meet the increasing demands in the clinics to understand and treat metabolic diseases, molecular information is needed about the effects of metabolites such as glucose on the amount and organization of the extracellular matrix, and on the activity of integrin cell surface receptors for extracellular matrix. Importantly, recent bio-medical research conducted by groups in Geneva (Pinon et al., 2014) and Princeton (Miller et al., 2014) has revealed key mechanistic interactions between an increased uptake of metabolites and the deterioration of tissue function through fibrosis. In addition, research conducted at the level of the integrin receptors (in the Wehrle-Haller lab) proposes that the metabolic state of a cell, exemplified by either aerobic or anaerobic decomposition of glucose, strongly influences the function of these integrin receptors. The consequences are either strongly-adherent and highly-signaling cells under low glucose conditions, or the enhanced deposition and remodeling of extracellular matrix under high glucose conditions. independently, research in the Schwarzbauer lab showed that high glucose conditions stimulate assembly of the extracellular matrix protein fibronectin and that this fibronectin matrix serves as a template for accumulation of type IV collagen, which is a hallmark of fibrosis in vivo.

The goal of this application is for our research teams to join forces in order to explore the mechanistic details of integrin receptor unction in response to the metabolic state of cells, and to link glucose-induced changes in integrin function to the pathological eposition of extracellular matrix. This research will identify new regulatory mechanisms acting at the cell (cytoplasmic adapter for ntegrins) and tissue levels (functional state of the matrix) and suggest new therapeutic targets, diagnostic markers and potentially new drugs designed to revert or identify pathological changes in the tissue. Metabolic effects on cell-matrix interactions are directly related to diseases such as diabetes, chronic inflammation, and nerve and muscle degeneration. Thus, our joint project will have a great socio-economic impact for our society and will hopefully serve as a seed to attract other research groups from our universities to investigate the importance of this mechanism in cancer and cardiovascular disease.

Diabetic retinopathy is a common complication of diabetes and a leading cause of blindness in adults. The high blood glucose levels that occur in diabetes damage the blood vessels of the retina leading to excess vascular permeability, retinal and macular edema and on
the long run blindness. The effects of diabetes can cause blood vessels to swell and leak or, in some cases, new blood vessels grow abnormally on the retina. One of the most prominent alterations in diabetic microangiopathy is the glucose-induced thickening of the extracellular matrix (ECM) around the retinal capillaries. The ECM is a complex protein network that provides scaffolding and structural support for cells and organs. Collagens are the most abundant ECM proteins in our bodies. In blood vessels, collagen forms a three-dimensional network for attachment of the endothelial cells that form the blood vessel wall. Other major ECM proteins include fibronectin, laminin, and proteoglycans. Fibronectin is of vital importance since it is required for formation of blood vessels during embryonic development.

Thickening of the blood vessel ECM is a dynamic process that reflects changes in turnover of matrix components combined with high-glucose-induced increases in synthesis of collagen, fibronectin, and other ECM proteins by the vascular cells. The exact mechanism
through which this happens has not been elucidated. Most studies in diabetes have focused on cellular abnormalities, while few have investigated the ultrastructural alterations that result in the thickened vascular wall or its impact on ECM porosity and capillary leakage. One potential clue relates to lysyl oxidase (LOX), an extracellular enzyme that controls collagen maturation in the ECM and stabilizes newly-formed ECMs through the formation of LOX-mediated crosslinks. Chronopoulos et al has shown that high glucose increases LOX expression and activity by retinal endothelial cells in culture and this excess LOX accumulates in the blood vessel walls in the retina [1]. The Schwarzbauer lab has recently shown that assembly of a fibronectin- and collagen IV-rich matrix is stimulated by high glucose through a process that involves increased activity of fibronectin receptors on the cell surface [2]. LOX has also been reported to function
inside the cell where it has been linked to changes in gene expression including upregulation of fibronectin [3]. These findings suggest a novel hypothesis to explain glucose-induced ECM thickening in the retina, namely, that upregulation of intracellular LOX activates expression of fibronectin, and perhaps collagen, which in combination with increased receptor activity, leads to excess production and deposition of ECM components. LOX also binds directly to fibronectin [4], so it could play a dual role by binding to fibronectin matrix, stabilizing it, and promoting ECM accumulation and vessel wall thickening.

We have devised a limited set of preliminary experiments that can be accomplished with Seed Grant funds to help us refine our hypothesis.

1. We will analyse the upregulation of LOX, fibronectin and collagen IV expression resulting from high glucose conditions/VEGF substitution in cultured retinal endothelial cells in as well as in retinas of diabetic rats. A correlation in protein localization within tissues and in the timing of protein expression changes in cell culture will support our hypothesis that LOX might be involved in the upregulation of ECM proteins.
2. We will determine whether LOX downregulation in diabetic rat retinas decreases fibronectin and collagen IV localization in the retinal vessel wall and whether reduced LOX (by means of siRNA or PEDF substitution) in cultured retinal cells leads to changes in fibronectin
   and collagen gene expression. Reduced levels of fibronectin and/or collagen in tissues or cells in which LOX has been downregulated experimentally will support a role for LOX in the upregulation of these proteins in the retina.