Research Abstract:
My research has three major focuses. The first deals with the roles of basement membranes, a specialized extracellular matrix, in embryonic development, organ function, and disease. Of particular interest are members of the laminin and collagen IV families and their roles in the kidney. We identified developmental transitions in laminin and collagen IV chain isoform expression which parallel the stages of kidney development. We have shown using knockout mice that model distinct human genetic kidney diseases that these transitions are critical for maturation and function of the glomerular basement membrane, a component of the kidney’s filtration apparatus. One interest of the lab is to define exactly what structure—cell or matrix—serves as the kidney’s filtration barrier. We also study the role of laminins and collagen IV chains in the intestine, lung, and placenta.
My second major interest is to define the mechanism whereby the mouse discs large homolog 1, a PDZ scaffolding protein, mediates normal development and function of the ureter. In the absence of DLG1, ureteric smooth muscle cells are misaligned, leading to impaired transportation of urine from the kidney to the bladder. This hydroureter/hydronephrosis defect is a common problem in children.
My third major interest concerns the role of fatty acid transport protein 4 (FATP4) in skin and hair development. We discovered that mutation of FATP4 results in “wrinkle free” mice. These mice have very tight, thick skin and die shortly after birth because they are unable to breathe properly. In addition, grafted skin from the mutant exhibits impaired hair growth. We are now using biochemical, cell biological, and mass spectrometric techniques to determine the mechanism whereby FATP4 activity leads to normal skin development, normal hair growth, and normal sebaceous gland structure and function.
Selected Publications:
Harvey SJ, Jarad G, Cunningham J, Goldberg S, Schermer B, Harfe BD, McManus MT, Benzing T, and Miner JH. Podocyte-specific deletion of Dicer alters cytoskeletal dynamics and causes glomerular disease. J. Amer. Soc. Nephrol. 2008 (In Press).
Mahoney ZX, Stappenbeck TS, and Miner JH. Laminin α5 influences the architecture of the mouse small intestine mucosa. J. Cell Sci. 2008 121:2493-2502.
Harvey SJ, Jarad G, Cunningham J, Rops AL, van der Vlag J, Berden JH, Moeller MJ, Holzman LB, Burgess RW, and Miner JH. Disruption of glomerular basement membrane charge through podocyte-specific mutation of agrin does not alter glomerular permselectivity. Am. J. Pathol. 2007 171:139-152.
Moulson CL, Lin MH, White JM, Newberry EP, Davidson NO, and Miner JH. Keratinocyte-specific expression of fatty acid transport protein 4 rescues the wrinkle free phenotype in Slc27a4/Fatp4 mutant mice. J. Biol. Chem 2007 282:15912-15920.
*Mahoney ZX, *Sammut B, Xavier RJ, Cunningham J, Go G, Brim K, Stappenbeck TS, Miner JH†, and Swat W†. Discs-large homolog 1 (Dlgh1) regulates smooth muscle orientation in the mouse ureter. Proc Natl Acad Sci USA 2006 103:19872-19877. †Co-corresponding authors.
Last Updated: 08/18/2008 |