Kidney disease is worldwide health problem that is becoming increasingly prevalent. Primary glomerular disease, both acquired and genetic, represents a significant proportion of these cases. We are interested in understanding the makeup of the glomerular filtration barrier and how it becomes damaged and leaky to plasma proteins. Our focus over the last sixteen years has been to investigate the composition and function of the glomerular basement membrane (GBM), a specialized extracellular matrix that is an integral component of the filtration barrier. The GBM contains laminin, collagen IV, nidogen, and the heparan sulfate proteoglycan agrin. Our studies of mice lacking the laminin beta2 chain suggests that the GBM itself serves as a barrier to albumin and protects podocytes from the injurious effects of plasma proteins, as mice lacking laminin beta2 develop nephrotic syndrome and renal failure. Mutations in human LAMB2 have also been shown to cause kidney disease;null mutations cause Pierson syndrome (congenital nephrotic syndrome with ocular and nervous system abnormalities), whereas missense mutations cause congenital nephrotic syndrome with less severe extrarenal manifestations. Our recent studies have shown that some of these missense mutations impair secretion of laminin-521 into the GBM, and that increased secretion of even mutant forms could be beneficial for patients carrying such mutations. The focus of this proposal is to find methods to ameliorate kidney disease in patients with GBM defects due to laminin abnormalities and to better understand the role of laminin polymerization in GBM structure and function. To accomplish this, we will 1) perform high throughput screens of drug libraries to find compounds that can promote secretion of mutant LAMB2 chains in vitro;2) test these compounds in vivo in our mouse models expressing mutant laminin beta2 chains to look for improved secretion and an improved filtration barrier;and 3) characterize activity and function of a human LAMB2 mutation that affects laminin polymerization. The results of these studies will provide important new insights into laminin and basement membrane biology and lead to potential therapies for human glomerular disease involving GBM defects.
Kidney disease is huge worldwide health problem that is becoming increasingly prevalent, and primary glomerular disease represents a significant proportion of these cases. The focus of this proposal is laminin-521, a component of the glomerular basement membrane that is required for a proper filtration barrier but is defective in some children with genetic kidney disease. The goal of this proposal is to investigate mechanisms whereby the kidney disease in these patients can be ameliorated by improving secretion and/or incorporation of laminin into the kidney's filtration apparatus.
|BrÃ¤hler, Sebastian; Yu, Haiyang; Suleiman, Hani et al. (2016) Intravital and Kidney Slice Imaging of Podocyte Membrane Dynamics. J Am Soc Nephrol 27:3285-3290|
|Yu, Haiyang; Artomov, Mykyta; BrÃ¤hler, Sebastian et al. (2016) A role for genetic susceptibility in sporadic focal segmental glomerulosclerosis. J Clin Invest 126:1067-78|
|Kim, Yeawon; Lee, Heedoo; Manson, Scott R et al. (2016) Mesencephalic Astrocyte-Derived Neurotrophic Factor as a Urine Biomarker for Endoplasmic Reticulum Stress-Related Kidney Diseases. J Am Soc Nephrol 27:2974-2982|
|Jarad, George; Knutsen, Russell H; Mecham, Robert P et al. (2016) Albumin contributes to kidney disease progression in Alport syndrome. Am J Physiol Renal Physiol 311:F120-30|
|Malone, Andrew F; Funk, Steven D; Alhamad, Tarek et al. (2016) 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 :|
|Lin, Congxing; Werner, Ralf; Ma, Liang et al. (2016) Requirement for basement membrane laminin Î±5 during urethral and external genital development. Mech Dev 141:62-9|
|Miner, Jeffrey H (2016) Podocyte biology in 2015: New insights into the mechanisms of podocyte health. Nat Rev Nephrol 12:63-4|
|Randles, Michael J; Collinson, Sophie; Starborg, Tobias et al. (2016) Three-dimensional electron microscopy reveals the evolution of glomerular barrier injury. Sci Rep 6:35068|
|Miner, Jeffrey H (2015) Preface. Curr Top Membr 76:xi-xiv|
|Chung, Jun-Jae; Huber, Tobias B; GÃ¶del, Markus et al. (2015) Albumin-associated free fatty acids induce macropinocytosis in podocytes. J Clin Invest 125:2307-16|
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