Academic journal article International Journal of Child Health and Human Development

Polycystic Kidney Disease: A Model for Treating Genetic-Based Chronic Diseases

Academic journal article International Journal of Child Health and Human Development

Polycystic Kidney Disease: A Model for Treating Genetic-Based Chronic Diseases

Article excerpt

Chronic Diseases in children are the result of unique sets of genetic, environmental, and behavioral interactions. Given genetic differences between outbred populations (humans), it has been valuable to study monogenetic disorders in experimental animals. Particularly in rodents, in which modem tools of genetic manipulation have been well-developed, unique models have given insight into the basic genetic pathways modified in chronic diseases and led to early translation of such aberrant pathways into therapies for humans. Genetic Polycystic Kidney Diseases (PKD), such as Autosomal Dominant PKD (ADPKD) and Autosomal Recessive PKD (ARPKD) are chronic diseases which start in childhood and produce significant morbidity and mortality. Worldwide, ADPKD and ARPKD affect over 13 million individuals. The cost of treatment of dialysis and transplantation alone for PKD in the USA is > $3.5 billion annually. This does not include the devastating effects of PKD on families in terms of "vulnerable children," parental anxiety and guilt, and morbidity (including days lost from school) for medical complications. Currently, there is no disease-specific therapy for either ADPKD or ARPKD.

Through the development of unique rodent models of PKD, genetic "disease pathways" can be identified utilizing all of the tools of modem genomics. The use of such experimental models of PKD will be briefly reviewed in this presentation. It will be demonstrated that these genetic models share strong phenotypic similarities with children with the chronic disease manifestations of PKD. Both genetic animal models and children with PKD demonstrate the same cellular abnormalities. These include: a) alterations of the Epidermal Growth Factor (EGF) family of ligands and receptors; b) aberrant tyrosine kinase activity of renal tubular and biliary c-src and its downstream signaling; and c) modified G-protein signaling with consequent alterations in c-AMP and intracellular calcium. …

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