Jeffrey H. Miner, Ph.D.

Internal Medicine
Cell Biology and Physiology

Molecular Cell Biology Program
Developmental, Regenerative and Stem Cell Biology Program

Research Abstract:

My research focuses on two rare but important genetic kidney diseases, Alport syndrome and Pierson syndrome. Each is a disease of the glomerular basement membrane (GBM), a major component of the kidney’s glomerular filtration barrier. Basement membranes are specialized extracellular matrices that play critical roles in embryonic development, organ function, and disease. Of particular interest are members of the laminin and collagen IV families and their roles in the GBM. We have generated Col4 and laminin knockout mice that model distinct human genetic kidney diseases (Alport and Pierson syndromes, respectively) and used them to show that laminin and collagen IV are critical for maturation and function of the GBM. One interest of the lab is to define exactly what structure—cell or matrix—serves as the kidney’s filtration barrier. We are using our mouse models of human kidney disease to test potential therapies with both NIH and industry funding.

We have recently been using CRISPR/Cas9 technology in vivo to introduce mutations found in human Pierson into the mouse to investigate mechanisms of pathogenesis. These experiments led us to discover novel genetic interactions between the laminin and collagen IV networks in the GBM and to a serendipitous in frame laminin mutation that causes a chronic nephrotic syndrome. We are using these mouse models to test innovative therapies aimed at restoring the structure and function of the GBM as proofs-of-principle to slow kidney disease progression in patients.

We are employing super-resolution fluorescence microscopy (STORM) to analyze mouse and human kidney sections in normal and various disease states. We are characterizing changes in the position of extracellular matrix proteins in the GBM and alterations in shape and cytoskeleton of the adjacent specialized epithelial cells, which are called podocytes. This has led to a new understanding of how the glomerular filtration barrier becomes defective in the setting of injury.

Selected Publications:

Lin, M-H, Miller, JB, Kikkawa, Y, Suleiman, HY, Tryggvason, K, Hodges, BL, and Miner, JH. Laminin-521 protein therapy for glomerular basement membrane and podocyte abnormalities in a mouse model of Pierson syndrome. J. Amer. Soc. Nephrol. 29: 1426-1436 (2018).

Funk, SD, Bayer, RH, Malone, AF, McKee, KK, Yurchenco, PD, and Miner, JH. Pathogenicity of a human laminin beta2 mutation revealed in models of Alport syndrome. J. Amer. Soc. Nephrol. 29: 946-960 (2018). PMCID: PMC5827610

Suleiman, HY, Roth, R, Jain, S, Heuser, JE, Shaw, AS*, and Miner, JH*. Injury-induced actin cytoskeleton reorganization in podocytes revealed by super-resolution microscopy. JCI Insight 2(16): 94137 (2017). PMCID: PMC5621879

Malone, AF, Funk, SD, Alhamad, T, and Miner, JH. Functional assessment of a novel COL4A5 splice region variant and immunostaining of plucked hair follicles as an alternative method of diagnosis in X-linked Alport syndrome. Pediatr. Nephrol. 32: 997-1003 (2017). PMCID: PMC5400701

Lin, C, Werner, R, Ma, L, and Miner, JH. Requirement for basement membrane laminin alpha5 during urethral and external genital development. Mech. Dev. 141: 62-69 (2016). PMCID: PMC4995130

Jarad, G, Knutsen, RH, Mecham, RP, and Miner, JH. Albumin contributes to kidney disease progression in Alport syndrome. Am. J. Physiol. Renal Physiol. 311: F120-130 (2016). PMCID: PMC4967167

Lin, M-H and Miner, JH. Fatty acid transport protein 1 can compensate for fatty acid transport protein 4 in the developing mouse epidermis. J. Invest. Dermatol. 135: 462-470 (2015). PMCID: PMC4289464

Lin, X, Suh, JH, Go, G, and Miner, JH. Feasibility of repairing glomerular basement membrane defects in Alport syndrome. J. Amer. Soc. Nephrol. 25: 687-692 (2014). PMCID: PMC3968506

Kim, ST, Ahn, S-Y, Swat, W, and Miner, JH. DLG1 influences distal ureter maturation via a non-epithelial cell autonomous mechanism involving reduced retinoic acid signaling, Ret expression, and apoptosis. Dev. Biol. 390: 160-169 (2014). PMCID: PMC4038003

Korstanje, R, Caputo, CR, Doty, RA, Cook, SA, Bronson, RT, Davisson, MT, and Miner, JH. A mouse Col4a4 mutation causing Alport glomerulosclerosis with abnormal collagen α3α4α5(IV) trimers. Kidney Int. 85: 1461-1468 (2014). PMCID: PMC4040157

Suleiman, H, Zhang, L, Roth, R, Heuser, JE, *Miner, JH, *Shaw, AS, and Dani, A. Nanoscale protein architecture of the kidney glomerular basement membrane. Elife 2013;2:e01149 (2013). PMCID: in process *Co-Corresponding Authors.

Last Updated: 5/7/2018 11:38:44 AM

In the developing kidney, nephron stem cells (green) are induced by the branching ureteric bud (red) to differentiate into filtration units (purple).
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