Objective
Objectives:
To identify the crystallin protein interaction sites involved in the aggregation that leads to cataract with the aim of designing small molecules or mimetics that block aggregation.
One of the hallmarks of aging is disease due cellular instability, the result of damage to macromolecular components. The most common of such diseases is cataract. Cataract is the most frequent cause of blindness in man and occurs inevitably with age, about 50% of the people 70 years of age suffer from significant loss of vision due to cataract. The high incidence of cataract results from one of the unusual properties of the lens: its mature fibre cells are incapable of macromolecular synthesis and damaged components cannot be replaced. For transparency, the lens depends on the short range interaction of its highly abundant structural proteins, making the lens particularly sensitive to protein misassembly. The built-in chaperone of the lens, alpha-crystallin, prevents aggregation of unfolding crystallins. The present theory is that cataract is irreversibly initiated, once the chaperone capacity of alpha-crystallin is exhausted. It is the objective of this RTD-project to determine the interaction sites through which the unfolding bta- and lacet-crystallins aggregate. The definition of such sites then allows the design of compounds that interact with these sites to prevent misassembly and thereby prevent or delay cataract.
To that end a combination of molecular biological, biochemical, cell biological and biophysical techniques will be used to determine
- the chaperone capacity of alpha-crystallin towards other human crystallins;
- the stability of the various human crystallins and the effect of post-translational modification (clipping, oxidation) there on the interaction between human crystallins;
- the structure of human crystallin (assemblies) Together the results should pinpoint the crystallin(s) most likely to initiate the cataractogenic process and the structural elements most likely to serve as interaction sites of structured unfolding intermediates.
In vivo, crystallin synthesis is regulated by ocular growth factors. Aberration in ocular growth factors, as a result of systemic disease or prolonged treatment with medication, could thus change the balance between alpha-crystallin and the bta- and lacet-crystallin and increase the likelihood of cataract. In vitro differentiating lens cultures will be used to determine the effect of growth factors in alpha, bta and lacet-crystallin synthesis, while the effect of changing the ratio of alpha to bta and lacet-crystallin on the likelihood of cataractogenesis will be assessed in transgenic mice strains. The transparency of the eye lens is the result of a fine tuning of interactions at different levels of organization. It is the aim of this RTD-project to determine how these interactions are disturbed and how misassembled proteins in the lens can be rescued before irreversible pathological changes occur. Keywords: cataract, lens, crystallins, protein aggregation.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- medical and health sciences basic medicine pharmacology and pharmacy pharmaceutical drugs
- natural sciences chemical sciences electrochemistry electrolysis
- natural sciences biological sciences biochemistry biomolecules proteins
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Coordinator
6525 ED Nijmegen
Netherlands
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