ERC FUNDED PROJECTS

Vitamin A supplementation (VAS) and vaccines are the most powerful tools to reduce child mortality in low-income countries. However, we may not use these interventions optimally because we disregard that the interventions may have immunomodulatory effects which differ for boys and girls and which may interact with the effects of other interventions. I have proposed the hypothesis that VAS and vaccines interact. This hypothesis is supported by randomised and observational studies showing that the combination of VAS and DTP may be harmful. I have furthermore proposed that VAS has sex-differential effects. VAS seems beneficial for boys but may not carry any benefits for girls. These findings challenge the current understanding that VAS and vaccines have only targeted effects and can be given together without considering interactions. This is of outmost importance for policy makers. The global trend is to combine health interventions for logistic reasons. My research suggests that this may not always be a good idea. Furthermore, the concept of sex-differential response to our common health interventions opens up for a completely new understanding of the immunology of the two sexes and may imply that we need to treat the two sexes differently in order to treat them optimally possibly also in high-income countries. In the present proposal I outline a series of inter-disciplinary epidemiological and immunological studies, which will serve to determine the overall and sex-differential effects of VAS and vaccines, the mechanisms behind these effects, and the basis for the immunological difference between boys and girls. If my hypotheses are true we can use the existing tools in a more optimal way to reduce child mortality without increasing costs. Thus, the results could lead to shifts in policy as well as paradigms.

1 686 043 €

Start date: 2010-01-01, End date: 2014-12-31

Prostate cancer is the most frequently diagnosed malignancy in the western male population and the associated socio-economic impact on healthcare is more than worrying. There is one key feature of confined (stage T2) prostate cancer that needs to be addressed with immediate urgency: its true aggressiveness. Not all cancers are life threatening and early diagnosis, although needed to improve outcome, will lead to overtreatment of patients with indolent prostate cancer resulting in unnecessary treatment-related morbidity. Therefore, methods to identify clinically significant forms of prostate cancer have to be developed. To pursue this, the initial assessment of the extent of the disease process (clinical staging) needs to be adequate. Obtaining pre-treatment representative tumor tissue (biopsies) is a major clinical challenge, as the disease is often multi-focal and heterogeneous. Accurate functional in vivo imaging modalities could guide these biopsies. Modern genomics technologies have identified numerous cancer cell-associated genetic markers being expressed in prostate cancer tissue or body fluids. Closing the gap between genomics and a non-invasive metabolic assessment of the in vivo prostate, we propose to identify new in vivo targets/biomarkers indicating confined prostate cancer aggressiveness with the underlying central hypothesis: early functional metabolic differences in different tumor foci determine whether it will grow into life-threatening prostate cancer or not. To track these early metabolic differences, the very latest magnetic resonance methodologies, including 13C MR of hyperpolarized metabolites and 1H- and 31P-MRSI of the in vivo human prostate at a field strength of 7 Tesla, will be further developed and implemented. In the well-established translational research environment at the host institution, potential new biomarkers translate into molecular diagnostics or imaging tools for an accurate individual assessment of cancer aggressiveness.

1 800 209 €

Start date: 2010-03-01, End date: 2015-02-28

A foremost health problem stems from the burden of degenerative diseases, including heart failure, neurodegeneration, retinal degeneration and diabetes, essentially linked to the aging of the human population and the incapacity of post-mitotic tissues to undergo efficient repair. This is an ambitious, highly innovative project aimed at developing an in vivo selection procedure, based on gene transfer of two genetic libraries cloned into Adeno-Associated Virus (AAV)-based vectors, for the identification of novel secreted factors or microRNAs providing benefit against various degenerative diseases. Two arrayed libraries will be generated, one coding for ~1,300 cDNAs from the mouse secretome, the other for all known microRNAs (~800 genes). Pools of vectors from each library will be obtained with serotypes suitable for in vivo transduction of different organs. The vectors will be injected in a series of mouse models of degenerative disorders involving damage to cardiomyocytes,, neurodegeneration, retinal degeneration and loss of beta-cells in the pancreas. The degenerative conditions will drive the selection for secreted factors or miRNA putatively preventing cell apoptosis, enhancing residual cell function or, in the best possible scenario, promoting tissue regeneration. This in vivo selection approach, which is supported by very encouraging preliminary results, has never been attempted before and is rendered possible by the property of AAV vectors to be produced at high titers, infect tissues at high multiplicity, persist in the transduced cells for prolonged period of times and efficiently express their transgenes in vivo. In addition to its final goal of identifying novel biotherapeutics, the project entails the successful achievement of several intermediate objectives and is expected to extend both technology and knowledge beyond the state-of-the art.

1 824 000 €

Start date: 2010-04-01, End date: 2015-03-31

Diabetes is a degenerative disease affecting millions of persons worldwide. A cure for diabetes depends on replacing the insulin-producing ²-cells in the pancreas that are destroyed by the disease. An attractive strategy to attain this goal is to convert liver adult cells of the same patient into pancreatic ²-cells. The liver and pancreas share many aspects of their early development and are specified in adjacent regions of the endoderm, possibly from a common bipotent progenitor cell. Therefore, conversion of liver to pancreas is conceivable and should imply only few steps backward to a common progenitor and little epigenetic changes. However, how pancreatic versus hepatic fate decision occurs during development is still poorly understood. The aim of this proposal is two fold: to perform lineage analysis, and to study developmental regulators of pancreatic versus hepatic fate decision. We will use new genetic tools, based on the GFP and photoconvertible Kaede fluorescent proteins, to address: i. if the liver and pancreas arise from a common bipotent progenitor cell; ii. to trace in vivo; and iii. molecularly profile the presumptive precursor cell and its descendants in the mouse embryo. Our previous studies have identified target genes of the GATA factors that might act as intrinsic developmental regulators of the pancreatic versus hepatic fate decision. Both intrinsic factors together with extrinsic regulators, such as BMP, will be studied. We will test their potential to promote lineage reprogramming of liver to pancreas using the mouse as well as mouse embryonic stem cells as model systems. Understanding how distinct cell types arise from common multipotent progenitor cells is a major quest in developmental biology. Our findings will elucidate the spatiotemporal mechanisms that control pancreas versus liver fate decision. In addition, they will provide the blueprint for lineage reprogramming of adult hepatic cells to pancreas in diabetes cell-therapy.

1 186 746 €

Start date: 2009-11-01, End date: 2014-10-31