TRANSCURE · Biomedical implications of epithelial transporters and channels
6РП — Действия „Мария Кюри“
- Период
- 2006-11-01 → 2008-10-31
- Финансиране от ЕС
- 80 000 €
- Участници
- 1
- Схема
- IRG
Линиите свързват координатора с партньорите. За проекти отпреди 2014 г. CORDIS не винаги дава точни координати. Тези точки са на ниво град или държава.
Накратко на български
Генът TRPV6 и неговите вариации влияят на начина, по който калцият преминава през клетките на червата и бъбреците. Разбирането на тези генетични промени помага да се обясни защо при някои хора се образуват бъбречни камъни.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Final Activity Report Summary - TRANSCURE (Biomedical implications of epithelial transporters and channels)
Kidney stone disease is a major health problem worldwide, with a lifetime incidence of 10%. Genetic factors appear to be involved since 40% of these patients have a positive family history. Idiopathic hypercalciuria is the most common abnormality observed in calcium stone formers. The intestinal and renal epithelial Ca2+ transport mechanisms are comprised of three steps: (i) apical Ca2+ entry via TRPV-calcium channels (transient receptor potential channels, subtype V), which is likely to be a rate-limiting step of transepithelial calcium transport; (ii) binding of Ca2+ to calbindin D which serves as an intracellular Ca2+ buffer, and (iii) basolateral calcium exit via the plasma membrane Ca2+ pump and/or the Na+/ Ca2+ exchanger. Steps 1 and 2 are induced by 1,25-dihydroxyvitamin D, the active form of vitamin D. The key molecules for the apical Ca2+ entry, TRPV5 and TRPV6, were previously identified by expression cloning from the kidney and small intestine, respectively. trpv5 knockout mice exhibited renal leak hypercalciuria with increased intestinal Ca2+ absorption due to a compensatory upregulation of trpv6. In humans, however, no phenotype-genotype relationship between TRPV5 polymorphisms and hypercalciuria has been observed so far, possibly due to this compensation. On the other hand, trpv6 knockout mice exhibited decreased intestinal Ca2+ absorption without obvious compensation by trpv5 in the intestine, resulting in secondary hyperparathyroidism. In our studies, we investigated the coding region of the TRPV6 gene in 170 Swiss Ca2+ stone formers. We found a haplotype containing three non-synonymous polymorphisms. Our functional analyses demonstrate that it produces a gain-of-function channel. Our results strongly indicate that genetic alterations of the TRPV6 gene are risk factors for hypercalciuria. The outcome of these proposed studies may help decrease the cost of medical treatment of kidney stone patients through the development of more specific treatment approaches that are based on knowledge of our TRPV and also citrate transporter molecules.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Membrane transporters and channels are an important class of proteins responsible for moving essential nutrients and minerals into and out of cells. After I pioneered the development of expression cloning for the identification of membrane transport proteins, my laboratory at Harvard Medical School subsequently identified and characterized a variety of nutritionally important epithelial transporters. These include transporters of iron, vitamin C, citrate, glutamate, amino acids and peptides, as well as epithelial calcium channels.With my return to Switzerland last summer, the efforts of my new lab at the University of Berne are being devoted to three major areas of research:1. epithelial calcium channels and pathophysiological implications;2. molecular physiology of iron transport;3. therapeutic applications of membrane transporters and channels.This Marie Curie Reintegration Grant will specifically allow me to elucidate the medical and pathological implications of the epithelial calcium channels TRPV5 and TRPV6. I propose to perform an in-depth genetic examination of the role of the TRPV5 and TRPV6 calcium channels in patients with idiopathic hypercalciuria (collaboration with Prof. Frey). Identification of disease-related variations of these genes may lead to the design of useful diagnostic tools for the examination of patients with Ca2+-related disorders. Furthermore, as a first step towards the development of therapeutic applications, I propose to develop specific inhibitors for the TRPV calcium channels.Our functional assays for the TRPV channels will be ideally suited for designing assays for high throughput screening to identify lead drugs for pharmaceutical developments of novel calcimimetics. The results from these studies may help develop treatment strategies for kidney stone patients through in-depth knowledge of the TRPV5 and TRPV6 calcium channels.
Оригинален текст от CORDIS (на английски).
Участници
- UNIVERSITÄT BERN · BERNКоординаторНиво градШвейцария
Връзки
Данни: CORDIS, © Европейски съюз