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Elucidation of the molecular and functional basis of disease phenotypes in the rat model

Final Report Summary - ELABORATE (Elucidation of the molecular and functional basis of disease phenotypes in the rat model)

High blood pressure, type 2 diabetes and inflammatory kidney disease are amongst the commonest of human disorders in present populations and are leading causes of morbidity and mortality from heart attacks, stroke and kidney failure. The ELABORATE project aimed to generate new insights into these conditions by studying rat models in which these disorders have been characterised over the past century, mainly in observational studies. With new gene-targeting tools, we aimed to understand more about the mechanisms of these common disorders, to identify new genes and pathways underlying these conditions, suggesting new drug targets that will lead to new strategies for disease prevention and treatment.

Building on work that the Principal Investigator has conducted over the past 20 years, with gene mapping and expression studies in rat models of high blood pressure, resistance to insulin action and autoimmune kidney disease, 20 new rat models were created by gene-targeting. The genes that were targeted were suspected as contributors to the pathogenesis of these disorders in the rat model and in humans. The 20 new rat lines were characterised in physiological and genetic studies. Several of them gave direct proof that the selected genes are causally implicated in the pathogenesis of insulin resistance, high blood pressure and inflammatory kidney disease in these rat models. Deletion of these genes in the rat model resulted in amelioration of the conditions in the rat, leading to the strong likelihood that inhibition of the corresponding human genes or pathways could be used to treat the related human conditions.

Examples of the successes of this approach in the ELABORATE project include the identification of several disease genes: Zip12, which causes high blood pressure in the circulation of the lungs; Cyp2j4, a gene causing inflammation and fibrosis in the kidney; and Cfb and Camk2n1, two genes that cause high blood pressure and insulin resistance. These results have led to pharmaceutical collaborations to test inhibitors of ZIP12 for treatment of human heart and lung disease, and new experiments to understand more precisely the mechanisms underlying kidney inflammation, blood pressure and insulin resistance. This has brought about new collaborations, and the development of grant awards and funding applications to use the resources developed in ELABORATE to test the identified genes for their potential to treat human diseases.

Overall, the achievements of this project have highlighted the value of rat models for the study of common, complex, human diseases. This project has: broken new ground in understanding disease mechanisms; identified drug targets that are entering clinical trials; spawned scientific collaborations in rat genetics across several institutions; and significantly progressed basic science research towards applicability in clinical practice and commercial drug development. Publications arising from this award will stand as a lasting record of the knowledge and information generated in this project that will serve as exemplars of work on the rat as a model organism, and for the potential to translate such work to the treatment of human disease.