ERC FUNDED PROJECTS

HIV is one of the most rapidly evolving organisms known. Understanding its evolutionary dynamics is essential for successful drug treatment or vaccine design. At the same time, this rapid evolution makes HIV an ideal model system to study fundamental problems in evolutionary dynamics: In HIV, one can directly observe evolution over genetic distances that correspond to millions of years of evolution in other organisms. This proposal combines time series of ultra-deep sequence data of HIV from individual patients, functional information on drug resistance, and methods from statistical physics to study evolution. The sequence data will observe the dynamics of the genotype distribution in the population, while the exceptionally well characterized biology of HIV will allow the assignment of functional significance to the observed genotypic changes. These two levels of description will be integrated by theoretical models that describe how selection on phenotypes feeds back on the genotype distribution. Specifically, we will determine the fundamental parameters of HIV evolution such as selection strength, recombination rates, and the patterns of genetic interactions from the time resolved data obtained by deep sequencing. We will use the data base of viral sequences that evolved in response to drug treatment to infer the fitness landscapes of drug resistance. These two projects will be integrated in a quantitative model of drug resistance evolution. In a third project, we will quantify how genetic interactions affect the formation of circulant recombinant forms of HIV. Using HIV as a model system, we will develop and test theories of multi-locus evolution, characterize fitness landscapes and genetic interactions, and quantify the impact of recombination on HIV evolution.

1 155 859 €

Start date: 2011-03-01, End date: 2016-02-29

"Immunological memory provides immunity against recurrent pathogens, but also can induce and regulate immunopathology. In chronic immune-mediated diseases, a ""pathogenic"" immunological memory probably is the essential driver of inflammation, refractory to physiological regulation and state-of-the-art therapeutic immunosuppression, and thus a challenge for the development of novel, curative therapeutic strategies. Despite its relevance, immunological memory is poorly understood. We recently discovered memory plasma cells and professional memory T helper cells, and their organisation by bone marrow stroma and the stroma of inflamed tissues. We have identified genes and regulating function and persistence of memory and effector cells in the resting state and in chronic immune reactions. Based on these intriguing, paradigm-breaking initial results, I propose to develop and lead a research program addressing the organisation and role of immunological memory in protective immunity and in immune-mediated diseases, on the systemic, cellular and molecular level. In particular, I propose to (1) analyse the homing of plasmablasts and T helper memory cell precursors to dedicated survival niches of the bone marrow or inflamed tissues, (2) identify the niches of CD8 memory cells and memory B cells, (3) analyse the cellular and molecular composition of memory niches, (4) decipher the molecular communication between stromal cells and immune memory cells, (5) analyse how memory/effector T helper cells are reactivated, (6) define the role of memory-phenotype T cells in the periphery, (7) analyse the role of twist1 and hop for persistence and function of pathogenic Th memory/effector cells, and (8) develop strategies to selectively delete pathogenic immune memory cells."

2 465 000 €

Start date: 2011-08-01, End date: 2016-07-31

Hepatocellular carcinoma (HCC) is caused by chronic hepatitis and is the third most common cause of cancer-related death worldwide, with a rising incidence in first world countries. To date no effective therapies other than liver transplantation are available for this disease. Previous studies have provided evidence that inflammatory signalling pathways (e.g. the NF-b pathway) are crucial modulators of liver cancer development. However, the exact mechanisms driving hepatitis-induced liver damage and cancer formation remain elusive. Among others, aberrant expression of cytotoxic cytokines is thought to be critically involved. We have recently shown that the inflammatory cytokines lymphotoxin (LT)  and  are specifically upregulated in livers of patients suffering from hepatitis C and B virus-induced liver inflammation or HCC and that liver specific expression of LT and  in mice (AlbLT) suffices to induce inflammation-induced liver cancer development. We could further demonstrate that this depended on the presence of functional lymphocytes. My proposal is pillared by three main approaches that all aim to elucidate the exact cellular and molecular mechanisms underlying chronic liver damage and HCC development in humans as well as in mouse models of inflammation- or carcinogen-induced liver cancer. First, we will identify the particular immune cell type(s) (e.g. B- or T-lymphocytes; macrophages; NK-T cells) involved in HCC development. Although inflammatory signalling and immune cells appear to be important in HCC development it remains elusive, which immune cell type(s) contribute to inflammation induced liver cancer development. Secondly, we will investigate how inflammatory signalling pathways induce chromosomal aberrations. It is known that inflammatory signalling cascades cause chromosomal aberrations; however, the detailed mechanisms by which this occurs are not fully understood. Additionally, we will determine how inflammatory signalling influences the pathways involved in DNA repair, replication and chromosomal segregation culminating in chromosomal aberrations and cancer. Finally, we will examine the role of oval cells in liver cancer formation. Oval cells, which are putative liver-cancer stem cells, differentiate into either hepatocytes or cholangiocytes, proliferate under inflammatory conditions, and are found within HCC. However, their exact functional role in liver carcinogenesis is unknown. We will biochemically characterize proliferating and HCC-associated ovals cells in mouse models of inflammation-induced HCC and in diseased human liver tissues. This will pave the way for the development of the first genetic tools to deplete or express genes in an oval cell-specific manner. The new scientific knowledge gained by these studies investigating how immune cells and inflammatory signalling induce chronic liver damage and cancer on a mechanistic level, and how oval cells contribute to HCC will provide the basis for future novel pharmacological approaches to treating inflammatory liver diseases and HCC in humans.

1 212 190 €

Start date: 2010-10-01, End date: 2015-09-30

The coordination of cellular behaviour that results in development involves the synchronization of many distinct patterning processes. A prime example of coordination at different levels is the process of lateral organ development. Firstly, a positioning system ensures that new organs initiate at the right locations. Secondly, gene expression must be patterned so as to define the different tissue types correctly. Lastly, specific patterns of localized growth must occur such that the organ develops to the correct size and morphology. How are these distinct processes regulated and what signals coordinate their patterning? By building on my recent work, this proposal aims, for the first time, to build an integrated understanding of how these distinct patterning processes arise and coordinate with one another, in the model plant species Arabidopsis thaliana. The proposal utilizes and extends the multispectral live-imaging techniques I pioneered as a postdoc and combines this approach with state-of-the-art transcriptomics and perturbation methods. Specifically, I aim to understand the regulatory links that coordinate dorsoventral patterning, cell polarity and morphogenesis at the shoot apical meristem (SAM) and during lateral organ development.

1 498 152 €

Start date: 2011-01-01, End date: 2015-12-31