ERC FUNDED PROJECTS

Modern telescopes like Herschel and ALMA open up a new window into molecular astrophysics to investigate a surprisingly rich chemistry that operates even at low densities and low temperatures. Observations with these instruments have the potential of unraveling key questions of astrobiology, like the accumulation of water and pre-biotic organic molecules on (exo)planets from asteroids and comets. Hand-in-hand with the heightened observational activities comes a strong demand for a thorough understanding of the molecular formation mechanisms. The vast majority of interstellar molecules are formed in ion-neutral reactions that remain efficient even at low temperatures. Unfortunately, the unusual nature of these processes under terrestrial conditions makes their laboratory study extremely difficult. To address these issues, I propose to build a versatile merged beams setup for laboratory studies of ion-neutral collisions at the Cryogenic Storage Ring (CSR), the most ambitious of the next-generation storage devices under development worldwide. With this experimental setup, I will make use of a low-temperature and low-density environment that is ideal to simulate the conditions prevailing in interstellar space. The cryogenic surrounding, in combination with laser-generated ground state atom beams, will allow me to perform precise energy-resolved rate coefficient measurements for reactions between cold molecular ions (like, e.g., H2+, H3+, HCO+, CH2+, CH3+, etc.) and neutral atoms (H, D, C or O) in order to shed light on long-standing problems of astrochemistry and the formation of organic molecules in space. With the large variability of the collision energy (corresponding to 40-40000 K), I will be able to provide data that are crucial for the interpretation of molecular observations in a variety of objects, ranging from cold molecular clouds to warm layers in protoplanetary disks.

1 486 800 €

Start date: 2012-09-01, End date: 2017-11-30

Brain tumors represent an extremely heterogeneous group of more than 100 different molecularly distinct diseases, many of which are still almost uniformly lethal despite five decades of clinical trials. In contrast to hematologic malignancies and carcinomas, the cell-of-origin for the vast majority of these entities is unknown. This knowledge gap currently precludes a comprehensive understanding of tumor biology and also limits translational exploitation (e.g., utilizing lineage targets for novel therapies and circulating brain tumor cells for liquid biopsies). The BRAIN-MATCH project represents an ambitious program to address this challenge and unmet medical need by taking an approach that (i) extensively utilizes existing molecular profiles of more than 30,000 brain tumor samples covering more than 100 different entities, publicly available single-cell sequencing data of normal brain regions, and bulk normal tissue data at different times of development across different species; (ii) generates unprecedented maps of normal human CNS development by using state-of-the art novel technologies; (iii) matches these molecular portraits of normal cell types with tumor datasets in order to identify specific cell-of-origin populations for individual tumor entities; and (iv) validates the most promising cell-of-origin populations and tumor-specific lineage and/or surface markers in vivo. The expected outputs of BRAIN-MATCH are four-fold: (i) delivery of an unprecedented atlas of human normal CNS development, which will also be of great relevance for diverse fields other than cancer; (ii) functional validation of at least three lineage targets; (iii) isolation and molecular characterization of circulating brain tumor cells from patients´ blood for at least five tumor entities; and (iv) generation of at least three novel mouse models of brain tumor entities for which currently no faithful models exist.

1 999 875 €

Start date: 2019-05-01, End date: 2024-04-30

It is now widely accepted that tumors are composed of heterogeneous population of cells, which contribute to many aspects of treatment resistance observed in clinic. Despite the acknowledgment of the tumor cell heterogeneity, little evidence was shown about complexity and dynamics of this heterogeneity in vivo, mainly because of lacking flexible genetic tools which allow sophisticated analysis in primary tumors. We recently developed a very efficient mouse somatic brain tumor model which have a full penetrance of high grade glioma development. Combination of this model with several transgenic mouse lines allow us to isolate and track different population of cells in primary tumors, most importantly, we also confirmed that this can be done on single cell level. Here I propose to use this set of valuable genetic tools to dissect the cellular heterogeneity in mouse gliomas. First we will perform several single cell lineage tracing experiment to demonstrate the contribution of brain tumor stem cell, tumor progenitors as well as the relatively differentiated cells, which will provide a complete data sets of clonal dynamics of different tumor cell types. Second we will further perform this tracing experiment with the presence of conventional chemotherapy. Third we will perform single cell RNA sequencing experiment to capture the molecular signature, which determines the cellular heterogeneity, discovered by single cell tracing. This result will be further validated by analysis of this molecular signatures in human primary tumors. We will also use our established in vivo target validation approach to manipulate the candidate molecular regulators to establish the functional correlation between molecular signature and phenotypic heterogeneity. This project will greatly improve our understanding of tumor heterogeneity, and possibly provide novel approaches and strategies of targeting human glioblastomas.

2 000 000 €

Start date: 2015-06-01, End date: 2020-05-31

The three-dimensional organization of the genome, which strikingly correlates with gene activity, is critical for many cellular processes. The evolution of molecular techniques has allowed us to unveil chromatin structure at an unprecedented resolution. The most intriguing chromatin structures observed in animals are TADs (Topologically Associating Domains), which represent the functional and structural chromatin domains demarcating the genome. Structural proteins such as insulators proteins, on the other hand, have been shown to play crucial roles in mediating the formation of TADs. However, major structural factors relevant to chromatin structure are still waiting to be discovered in land plants. My preliminary work shows that TADs are widely distributed across the rice genome, and motif sequence analysis suggests the enrichment of plant-specific transcription factors at TAD boundaries, which jointly give rise to an exciting hypothesis that these proteins might be the long-sought-after insulators in land plants. By using various state-of-the-art molecular and computational tools, this timely project aims to fill a huge gap in plant functional genomics and substantially advance our understanding of three-dimensional chromatin structure. This project consists four major aims, which collectively will uncover the identities of plant insulator proteins and generate insights into the dynamics of structural chromatin domains during stress adaptation. Aim 1 will identify and characterize the stability and plasticity of functional chromatin domains in the rice genome during temperature stress adaptation. Aim 2 will identify insulator elements and other structural features of chromatin packing in the Marchantia polymorpha genome from a structural genomics approach. Aim 3 will establish the role of candidate proteins as plant insulators. Lastly, Aim 4 will generate functional insights into the molecular mechanism by which plant insulators shape the three-dimensional genome.

1 498 216 €

Start date: 2018-01-01, End date: 2022-12-31