ERC FUNDED PROJECTS

Systemic sclerosis (SSc) is an autoimmune disease that culminates in excessive extra-cellular matrix deposition (fibrosis) in skin and internal organs. SSc is a severe disease in which fibrotic events lead to organ failure such as renal failure, deterioration of lung function and development of pulmonary arterial hypertension (PAH). Together, these disease hallmarks culminate in profound disability and premature death. Over the past three years several crucial observations by my group changed the landscape of our thinking about the ethiopathogenesis of this disease. First, plasmacytoid dendritic (pDCs) cells were found to be extremely frequent in the circulation of SSc patients (1000-fold) compared with healthy individuals. In addition, we observed that pDCs from SSc patients are largely dedicated to synthesize CXCL4 that was proven to be directly implicated in fibroblast biology and endothelial cell activation, two events recapitulating SSc. Finally, research aimed to decipher the underlying cause of this increased pDCs frequency led to the observation that Runx3, a transcription factor that controls the differentiation of DC subsets, was almost not expressed in pDC of SSc patients. Together, these observations led me to pose the “SSc immune postulate” in which the pathogenesis of SSc is explained by a multi-step process in which Runx3 and CXCL4 play a central role. The project CIRCUMVENT is designed to provide proof of concept for the role of CXCL4 and RUNX3 in SSc. For this aim we will exploit a unique set of patient material (cell subsets, protein and DNA bank), various recently developed in vitro techniques (siRNA for pDCs, viral over expression of CXCL4/RUNX3) and apply three recently optimised experimental models (CXCL4 subcutaneous pump model, DC specific RUNX3 KO and the SCID/NOD/rag2 KO mice). The project CIRCUMVENT aims to proof the direct role for Runx3 and CXCL4 that could provide the final step towards the development of novel therapeutic targets

1 500 000 €

Start date: 2012-08-01, End date: 2017-07-31

"This project investigates how growing reliance on housing markets and family property wealth in meeting welfare and security needs is transforming contemporary welfare states. Home ownership normally constitutes a primary family node for the delivery and exchange of shelter, informal care and asset wealth, reducing household dependency on the state. Different modes of housing thereby influence welfare system development overall. In recent decades, increasing market values enhanced perceptions of housing property as a form of social security. Meanwhile, governments have encouraged home purchase as a means for households to accumulate housing assets, thereby insuring themselves against hardship. Understanding the role of housing tenure transformations in welfare system restructuring or the impact of housing markets on welfare regimes is, however, poorly developed. This study breaks new ground by examining how housing markets and welfare systems interact in different regime contexts. It focuses on welfare outcomes of housing as a private good and how housing sector differences influence both macro-state welfare arrangements and micro-household practices. This will advance understanding of how housing markets assume prominent roles in welfare system pathways and influence social stratification. This study will be realized through three sub-projects carried out in six countries that represent contemporary housing and welfare regimes: England, Germany, Romania, Italy, the Netherlands and Japan. 1) institutional studies and macro statistical comparisons will evaluate how frameworks of social and welfare security shape, and are shaped by, housing systems; 2) qualitative field studies will asses how families in different housing and welfare regimes perceive, use and exchange housing assets to enhance economic security and welfare capacity; 3) analyses of international panel data will address how households are affected by shifting welfare and housing market conditions."

1 279 786 €

Start date: 2012-02-01, End date: 2017-01-31

"This project aims to study institutions specialized in visualizing society. Such institutions have proliferated in recent decades. From regulatory bodies to auditing institutions and regimes of supervision, from monitoring agencies to surveillance apparatuses, social life is full of reflexive spaces specialized in the visualization of that social life. Much of social theory assumes that societies exist on the basis of a work of imagination, yet very little comparative cross-sectional work exists on such ‘social imagination’. Much can be learned about social life when the institutions it brings forth to observe that social life are observed sociologically. In four subprojects, this research investigates: 1) How societies are imagined through the visualization of the border between society and nature, particularly in the context of the assessment of global flows of goods in: a) measurements of climate change, and b) the visualization of the economy and its implicit understanding of nature as mediated through production; 2) How economic borders, risks and responsibilities are imagined by the regulation and oversight of global flows of capital; 3) How national societies are imagined by the social scientific measurement of global flows of persons, notably immigrants in the assessment of their integration; 4) How the social space of the EU is imagined by the surveillance of global flows of persons, notably irregular migrants, by means of specialized EU-databases. This project is innovative in three ways. First, it is the first comparative cross-sectional study of the professionalized practice of the ‘imaginary constitution of society’. Second, it integrates theories and methods from various fields. Third, it renews understanding of the practical assemblage of imagined collectives such as ‘national societies’, and contributes to ‘globalization theory’ by analyzing the everyday routinized ways in which ‘global assemblages’ produce plausible boundaries and localities."

1 353 255 €

Start date: 2012-09-01, End date: 2017-08-31

We are constantly protected by our adaptive immune system. Its functioning requires precise control of gene expression in lymphocytes, since deregulation can cause autoimmune diseases (affecting ~5% of our population) as well as allergic reactions (~9-16%, with increasing incidence). Post-transcriptional control of gene expression is crucial in many immune decisions, however the determinants of specificity in this type of regulation are less well defined. The recently described Rc3h1 or Roquin protein prevents the development of autoimmune disease in mice. Rc3h1 destabilizes the mRNA of the inducible costimulator (ICOS), a co-receptor on T cells. ICOS is critical in the germinal center reaction in which T cell help selects B cells making high affinity antibodies. However, the molecular interactions of this posttranscriptional regulation and the pathways that specify such repressor/target relations are unsolved, and they are the focus of my work in this proposal. Rc3h1 is an essential factor of peripheral T cell tolerance, whereas the role of its paralog Rc3h2 has not been addressed. We have recently shown that Rc3h1 is an RNA binding-protein that recognizes the 3’UTR of ICOS mRNA. Our preliminary data suggest that Rc3h2 is co-expressed in T cells and binds ICOS mRNA indistinguishably in vitro, however it does not repress ICOS. Major challenges are therefore to define how the Rc3h1/2 proteins recognize cis-elements in the RNA, which cofactors they require for repression and how these proteins exert diverse functions. My project proposes to pursue three aims: (1) to describe Rc3h1/2 target recognition in the T cell transcriptome, (2) to globally identify the essential genes in this pathway of post-transcriptional repression and (3) to analyze redundant and unique roles of Rc3h1 and Rc3h2 proteins in the mouse embryo, the hematopoietic system and in models of immunity and spontaneous development of autoimmune disease.

1 392 400 €

Start date: 2011-11-01, End date: 2016-10-31