Theme 3: Cell growth and differentiation / Developmental Disorders and Malignancies
Multi-level analysis is used to study the functional blueprint of all cellular decisions, a functional genomics approach is pursued that ranges from deciphering the genome in terms of actively transcribed genes under defined cellular circumstances (such as normal differentiation versus unregulated proliferation) to specific disease-linked genomic studies. Since the single cell cannot be viewed in isolation from its cellular surrounding, decisions within the cell need to be linked to external cues and constraints, and the translation of this approach within cells is at the core of research on signalling networks. In order to understand the molecules that convey the information packaged in the functional genomic blueprint as well as the signals from the cellular outside world, it is also necessary to gain a better understanding of the protein structure and design of these molecules that finally convey the growth and differentiation decisions. Valuable insights can be gained from investigating a specific differentiation programme and neural development is studied as a special case.
The research activities within this theme aim to:
- Unravel the molecular basis of cell behavior, which emanates from the genetic and epigenetic code contained in the nucleus in the context of health and disease (e.g. cancer, developmental disorders, intellectual disability, cognitive impairments, neurodegenerative disorders and age-related bone diseases).
- Elucidate protein structure and protein-protein interactions within cellular signaling pathways that control cell proliferation and differentiation.
- Exploit the potential of molecular chemistry to modify, design and mimic proteins and their building blocks with the purpose to modulate and analyze their activities and properties in the cellular environment.
Genetic & Epigenetic pathways of disease
To achieve our mission, members of the genetic and epigenetic subtheme are engaged in technology development. These range from single molecule studies of reconstituted model chromatin through elucidation of epigenetic marks on a genome wide level and the implementation of Next Generation Sequencing (NGS) in fundamental research as well as in a diagnostic setting. Important lines of research focus on the molecular and cellular aspects of tumorgenic pathways, development and function of the nervous system, and the basic mechanisms of including epigenetics. Epigenetic marks such as DNA methylation and histone modifications mark genomic regions for transcriptional activity or repression. The role of many epigenetic modifications in health and disease remains elusive. These epigenetic mechanisms are studied in the context of mammalian hematopoietic and embryonic stem cells, yeast, parasites (plasmodium) and vertebrate embryos (Xenopus). Another goal is to uncover the molecular pathways and processes that underlie normal functioning of the central nervous system (CNS; e.g. mental retardation, intellectual disability, autism, schizophrenia and brain tumours) and the neuro-sensory system (blindness, deafness). Cell-specific transgenic approaches are used to elucidate the roles of proteins of unknown function and to examine the (epi)genetic basis of neurodevelopmental psychopathological disorders. Another important topic is the study protein networks in ciliary structures that are disrupted in various heritable forms of blindness, deafness and combined deaf-blindness (Usher syndrome). Proteins have been identified in a protein network in photoreceptors that localizes to the transition zone of the ciliary axoneme of these cells, the connecting cilium. In addition, subsets of the network have been identified at the cilia of tissues, affected in associated phenotypes, like kidney, brain and inner ear. Finally, genetic and epigenetic research on intellectual disabilities makes extensive use of model organisms such as the mouse and especially the fruit fly Drosophila melanogaster to study neuropathological defects and to elucidate disrupted molecular and cellular processes. Created fly models for intellectual disability are developed for use in screens to identify genetic modifiers and small molecule drugs that can modulate the mutant phenotype with the ultimate goal to develop strategies for therapy. In oncology rapid developments in targeted therapy enable the introduction of findings from basic genomic research into clinical application, both for diagnostics and for disease definition. Especially in lymphoma and colorectal cancer this has led to pioneering work.
Chemical & Physical Biology
Structure and function of proteins and their complexes play crucial roles in virtually all RIMLS research projects. Understanding their role and interactions on a molecular level and in a cellular context is an ultimate goal of increasing importance.
1) At the molecular level this subtheme aims at optimally exploiting the potential of (bio)molecular chemistry to modify, design and mimic proteins and their building blocks with the purpose to modulate and analyse their activities and properties in the (sub)cellular environment. This is best illustrated by the following examples: (i) novel bio-orthogonal conjugation methods to study and interfere with biological processes; (ii) stimulus-responsive cell penetrating peptides; (iii) use of non-proteinogenic amino acids in diagnosis and treatment of disease; (iv) mimicking cellular synthetic processes in microenvironments; and (v) hybrid cell systems: incorporation of synthetic components into living cells.
2) At the cellular and multicellular level this theme deals with elucidation of protein structure and protein-protein interactions. Research topics are: (i) post-transcriptional events in gene expression; (ii) cellular signaling pathways; (iii) (de)activation mechanisms of tyrosine kinases and tyrosine phosphatases; (iv) external control of cellular proliferation and differentiation; and (v) molecular probing of vascular pathology and angiogenesis.