Jeffrey H. Miner, PhD, Washington University in Saint Louis

Jeffrey H. Miner, PhD

A major interest of the Miner laboratory is the role of basement membrane components in kidney function and disease, with particular emphasis on the glomerular basement membrane (GBM) as a component of the glomerular filtration barrier to albumin. Several genetic and acquired diseases of the kidney affect the GBM, causing thinning or thickening. They are focusing on the laminin and type IV collagen components of the GBM that are mutated in Pierson syndrome (a congenital nephrotic syndrome) and Alport syndrome (hereditary glomerulonephritis), respectively. They have produced knockout mice lacking relevant laminin or collagen IV chains to determine their functions in the kidney and elsewhere. They have also generated transgenic mice expressing mutant versions of laminin beta2 to understand why the mutations cause human kidney disease, using both standard transgenesis and CRISPR/Cas9-mediated appraoches. They have performed proof-of-principle studies to show that the abnormal GBM that is present in Alport syndrome can be normalized by restoring expression of the missing collagen IV network.

 

 

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References

  1. Miner JH, Cunningham J, Sanes JR: Roles for laminin in embryogenesis: Exencephaly, syndactyly, and placentopathy in mice lacking the laminin alpha5 chain. J Cell Biol 143: 1713-1723, 1998.
  2. Miner JH, Li C: Defective glomerulogenesis in the absence of laminin a5 demonstrates a developmental role for the kidney glomerular basement membrane. Dev Biol 217: 278-289, 2000.
  3. Miner JH, Patton BL, Lentz SI, Gilbert DJ, Snider WD, Jenkins NA, Copeland NG, Sanes JR: The laminin alpha chains: expression, developmental transitions, and chromosomal locations of alpha1-5, identification of heterotrimeric laminins 8-11, and cloning of a novel alpha3 isoform. J Cell Biol 137: 685-701, 1997.
  4. Shannon MB, Patton BL, Harvey SJ, Miner JH: A hypomorphic mutation in the mouse Laminin alpha5 gene (Lama5) causes polycystic kidney disease. J Am Soc Nephrol 17: 1913-1922, 2006.
  5. Kikkawa Y, Miner JH: Molecular dissection of laminin alpha 5 in vivo reveals separable domain-specific roles in embryonic development and kidney function. Dev Biol 296: 265-277, 2006.
  6. Kikkawa Y, Moulson CL, Virtanen I, Miner JH: Identification of the binding site for the Lutheran blood group glycoprotein on laminin alpha 5 through expression of chimeric laminin chains in vivo. J Biol Chem 277: 44864-44869, 2002.
  7. Kikkawa Y, Virtanen I, Miner JH: Mesangial cells organize the glomerular capillaries by adhering to the G domain of laminin alpha5 in the glomerular basement membrane. J Cell Biol 161: 187-196, 2003.
  8. Moulson CL, Li C, Miner JH: Localization of Lutheran, a novel laminin receptor, in normal, knockout, and transgenic mice suggests an interaction with laminin alpha5 in vivo. Dev Dyn 222: 101-114, 2001.
  9. Bolcato-Bellemin AL, Lefebvre O, Arnold C, Sorokin L, Miner JH, Kedinger M, Simon-Assmann P: Laminin alpha5 chain is required for intestinal smooth muscle development. Dev Biol 260: 376-390, 2003.
  10. Nguyen NM, Kelley DG, Schlueter JA, Meyer MJ, Senior RM, Miner JH: Epithelial laminin alpha5 is necessary for distal epithelial cell maturation, VEGF production, and alveolization in the developing murine lung. Dev Biol 282: 111-125, 2005.
  11. Nguyen NM, Miner JH, Pierce RA, Senior RM: Laminin alpha 5 is required for lobar septation and visceral pleural basement membrane formation in the developing mouse lung. Dev Biol 246: 231-244, 2002.
  12. St. John PL, Abrahamson DR: Glomerular endothelial cells and podocytes jointly synthesize laminin-1 and -11 chains. Kidney Int 60: 1037-1046, 2001.
  13. St. John PL, Wang R, Yin Y, Miner JH, Robert B, Abrahamson DR: Glomerular laminin isoform transitions: errors in metanephric culture are corrected by grafting. Am J Physiol Renal Physiol 280: F695-705, 2001.
  14. Pierce RA, Griffin GL, Mudd MS, Moxley MA, Longmore WJ, Sanes JR, Miner JH, Senior RM: Expression of laminin alpha3, alpha4, and alpha5 chains by alveolar epithelial cells and fibroblasts. Am J Respir Cell Mol Biol 19: 237-244, 1998.
  15. Meehan DT, Delimont D, Dufek B, Zallocchi M, Phillips G, Gratton MA, Cosgrove D: Endothelin-1 mediated induction of extracellular matrix genes in strial marginal cells underlies strial pathology in Alport mice. Hear Res 341: 100-108, 2016.
  16. Imanishi H, Tsuruta D, Tateishi C, Sugawara K, Kobayashi H, Ishii M, Kishi K: Spatial and temporal control of laminin-332 and -511 expressions during hair morphogenesis. Med Mol Morphol 47: 38-42, 2014.
  17. Kim ST, Adair-Kirk TL, Senior RM, Miner JH: Functional Consequences of Cell Type-Restricted Expression of Laminin alpha5 in Mouse Placental Labyrinth and Kidney Glomerular Capillaries. PLoS ONE 7: e41348, 2012.
  18. Suleiman, Miner, et al. "Nanoscale Protein Architecture of the Kidney Glomerular Basement Membrane." Elife, 2013.
  19. Kim, Suleiman, Shaw. "New approaches in renal microscopy: volumetric imaging and super- resolution microscopy." Curr. Opin. Nephrol. Hypertens, 2016.
  20. Suleiman, Miner, et al. "Injury-induced actin cytoskeleton reorganization in podocytes revealed by super-resolution microscopy." JCI Insight, 2017.
  21. Lin, Suleiman, Miner, et al. "Laminin-521 protein therapy for GBM and podocyte abnormalities in a mouse model of Pierson syndrome." J. Amer. Soc. Nephrol., 2018.