| Project 13 |
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Importance of selenium and selenoproteins for chondrogenic differenttiationProf. Schomburg (first supervisor), Prof. Seemann (second supervisor), Dr. Renko (mentor); Charité Selenium is an essential trace element needed for the biosynthesis of a small number of selenocysteinecontaining selenoproteins. Some of these proteins have been shown to exert enzymatic functions, and three selenoproteins, i.e., glutathione peroxidase 4 (GPx-4), thioredoxin reductase 1 and 2 (TxnRd-1, -2), have been proven to be essential for life (1). Selenium deficiency leads to a number of severe pathologies and developmental defects including Kashin-Beck disease, an endemic osteoarthritis. Moreover, we have recently characterized human patients with impaired selenoprotein expression who presented with a number of clinical phenotypes including delayed bone development (2). Many of the selenium-dependent health effects display some characteristic gender differences (1). In an attempt to analyze the importance of a regular selenium supply and selenoprotein expression pattern for chondrogenic differentiation, we aim to study primary chondrogenic cells in culture and analyse their response to a varying selenium supply in the presence or absence of inflammatory stimuli (3, 4). The function of specific selenoproteins during this process will be evaluated using transgenic overexpression or knockdown strategies. Histology in combination with functional, proteomic and trancriptomic profiling assays will be employed to characterize the effects on the molecular level. We expect to yield biochemical insights into both the mechanisms behind the effects of selenium and selenoproteins on development of chondrocytes and on the importance of a regular selenium status and undisturbed selenoprotein expression pattern during disease and regeneration of pathologies affecting the bones and joints. Moreover, this research is intended to provide the rationale for the design and interpretation of respective human epidemiological and intervention studies. Dumitrescu, A. M., Liao, X. H., Abdullah, M. S., Lado- Abeal, J., Majed, F. A., Moeller, L. C., Boran, G., Schomburg, L., Weiss, R. E., and Refetoff, S. (2005) Mutations in SECISBP2 result in abnormal thyroid hormone metabolism. Nat Genet 37, 1247-1252 Seemann, P., Schwappacher, R., Kjaer, K. W., Krakow, D., Lehmann, K., Dawson, K., Stricker, S., Pohl, J., Ploger, F., Staub, E., Nickel, J., Sebald, W., Knaus, P., and Mundlos, S. (2005) Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2. J Clin Invest 115, 2373-2381 Renko, K., Hofmann, P. J., Stoedter, M., Hollenbach, B., Behrends, T., Köhrle, J., Schweizer, U., and Schomburg, L. (2009) Down-regulation of the hepatic selenoprotein biosynthesis machinery impairs selenium metabolism during the acute phase response in mice. Faseb J, in press |
