|
Sub-themes: Energy and redox metabolism (Prof. B. Wieringa) and Membrane transport and intracellular motility (Prof. R. Bindels).
The study of disease at the molecular level – but in the context of the macromolecular world of cellular organelles, the intact cell, or organs and tissues in the entire organism – is central to the NCMLS. Intrinsic genetic problems or extrinsic factors causing cellular energy deprivation, ion and metabolite and water transport failure, toxic accumulation of intermediates, or ischemia and anoxia caused by cerebro-vascular obstruction due to a range of diseases, including cancer, neuropathy and myopathy, degenerative disorders like Alzheimer’s and Parkinson, ischemic/anoxic organ failure, exercise intolerance and fatigue or renal tubulopathy and retinopathy. In addition, for conditions such as obesity and type II diabetes as well as some aspects of ageing, it is well established that there is a direct connection to metabolism and molecular transport and motion.
Within this theme the NCMLS bundles studies in two areas: (a) Energy and redox metabolism and (b) Membrane transport and intracellular motility. There are links between these topics at many levels. Metabolites such as ATP and NAD(P)(H) produced in key pathways like glycolysis and mitochondrial respiratory complexes are consumed as fuel or needed as co-factors for ion-transport ATPases or drug-transporters and the acto-myosin motor and sliding machinery involved in organelle dynamics and cell movements. Renal disease, cardiomyopathy, brain and muscle disorders have been demonstrated to be caused by defects in the production or assembly of ATPases, water channels, or the mitochondrial machinery. Defects in metabolic signalling are often involved.
|
|
Focusing on the central ‘energy and redox’ sub-theme of metabolism provides scientists at the NCMLS a strong asset in the international research competition and brings extra value to the international collaborations. Because participating laboratories are in close physical interaction scientists can easily share data, materials and ideas. An impetus for this new collaboration is the inclusion of various scientists from the Microscopic Imaging Centre, the Centre for Molecular and Biomolecular Informatics (CMBI) and the Nijmegen Centre for Mitochondrial Disorders (NCMD). A strong focus for research in the coming years will be the ‘imaging’ of ATP/ADP/AMP and NAD(P)H concentration and fate with existing and new-to-develop biosensor reporters in combination with fluorescence microscopy, the ‘imaging’ of metabolite fate with MRS and MRI and the use of new strategies to follow mitochondrial shape and activity, as reporters and determining actors in cellular metabolic state and viability. The integrat ion of “4-D” imaging and simultaneous recording of the behaviour of small molecules and macromolecular assemblies and cellular organelles remains therefore an important future challenge. Use of bioinformatics for cellular energetics pathway and response prediction and for assessing findings with genomic array profiling and proteomic procedures is another challenge. Furthermore, another major line of continuous importance will be the design and use of cell and animal models for disease. Ultimately, we aim to better understand the principles of (biochemical) adaptation to energy and redox stress, in order to better define ‘healthy responses within the normal physiological range’ and the ‘pathophysiological thresholds’ for disease manifestation, when mitochondrial function or energy transfer pathways are compromised by genetic or environmental stress.
|
|
Transport of water, solutes and metabolites plays a fundamental role in cellular and whole body homeostasis. ATP-consuming ion pumps generate cellular gradients which energise the transport of solutes and water by channels, (co)transporters and exchangers. Transport proteins currently studied within this subtheme are sodium (or hydrogen) and potassium ATPases, aquaporin water channels, transient receptor potential channels, organic anion transporters and sodium cotransporters. These transporters are involved in a whole range of diseases in organs such as brain, muscles, kidney, liver and bone. Now, most transport systems have been characterised at the molecular and cellular level, and the 3D molecular structure of a few transporters has recently been unravelled. We are beginning to understand how molecular events at the transporter level account for the physiological responses in cells, organs and the whole body. A new challenge will be to analyse the integrated network of signalling pathways underlying (hormonal) regulation of transport events at various stages ranging from gene regulation, routing of newly synthesised proteins towards the plasma membrane and control of activity. In addition, our theme will develop and implement new tools to tackle the outlined scientific goals including life time imaging, large scale screening assays at the mRNA and protein level, application of small interference RNA libraries, conditional knockout models, bioinformatics and functional analysis at the molecular level. The ultimate aim of our subtheme is to provide a molecular basis to understand, diagnose and ultimately cure inherited and acquired diseases of transport proteins such as channelopathies. To reach this aim, research integrates fundamental and clinical studies conducted at the genetic (gene defects, polymorphisms), molecular (transport and associated proteins), cellular (established model systems, isolated and transfected cells) and organism (conditional) knockout models) level. The participating laboratories come together frequently on a formal (regularly scheduled meetings) and informal (close localisation in adjacent rooms or buildings) basis that has already provided a solid basis to exchange data and ideas, and to establish collaborative research projects. This focused and stimulating approach has already offered the participating scientists a significant visibility within the international scientific community and has established successful international collaborations. The ongoing research projects are thoroughly anchored in the various local institutes including the Microscopic Imaging Centre, the Centre for Molecular and Biomolecular Informatics, the Top Centre for Genetic and Metabolic disorders and the Nijmegen Centre for Molecular Life Sciences. Disciplines of major interest include Cell Physiology, Pharmacology, Medical Biochemistry, Human Genetics and Paediatrics.
|
|
| |
Contact
|
Postal address:
259 NCMLS
P.O. Box 9101
6500 HB Nijmegen
The Netherlands
Visiting address:
Geert Grooteplein 28
6525 GA Nijmegen
T: +31 (0)24 361 07 07
F: +31 (0)24 361 09 09
E: Info@ncmls.ru.nl
I: www.ncmls.eu
|
|
Route
|
|
|
Search for employees
|
|
|
