Wellcome Trust PhD Programme for Clinicians at the University of Edinburgh: Structural and functional changes in the distal convoluted tubules of the kidney in mouse models of hypertension. (360G-Wellcome-090387_Z_09_Z)

I will ask: how do changes in the structure and function of the distal convoluted tubule of the kidney contribute to hypertension in mouse models? I will develop methods for defining and quantifying these changes and then use these to interrogate a hypertensive mouse model that demonstrates abnormal DCT morphology, the 11?-hydroxysteroid dehydrogenase null mouse (Hsd11b2 ?/?). My key goals are: 1) to define the ontogeny of the DCT in wild-type and Hsd11b2 ?/? mice by histological, ultra-structural and immunohistochemical characterisation 2) to create mouse reporter strains in which fluorescent proteins under the control of the promoters for the gene encoding the thiazide-sensitive transporter, Slc12a3 and Hsd11b2 are used to delineate the DCT and the mineralocorticoid-sensitive distal nephron respectively 3) to use these reporter strains to characterise changes in the DCT in response to salt-loading in wildtype, Hsd11b2 +/? and Hsd11b2 ?/? mice 4) to determine the functional consequence of cellular changes in the DCT of Hsd11b2 ?/? mice using whole-organism renal function studies and single-nephron micropuncture 5) to determine the causes of cellular changes in the DCT in Hsd11b2 ?/? mice by applying microarray expression profiling to cells isolated from reporter strains using laser capture microdissection