Glomerular Basement Membrane (GBM) is a key component of the filtration system of the kidney and structural and functional defects in this GBM are associated with many kidney diseases. The rate of GBM turnover and its regenerative potential is unknown. Type IV colagen is the most abundant protein present in the GBM. The basic unit of type IV collagen is a triple helical protomer derived from three 1-chains. With six known isoforms of type IV collagen (11-16), theoretically many combinations of protomers are possible. Type IV collagen in the glomerular basement membrane (GBM) is predominantly composed of 13, 14 and 15 chains, with 13 chain of type IV collagen being most abundant. Mutations in any one of these chains in Alport syndrome (a condition associated with progressive kidney disease, occasional sensorineural hearing loss and anterior lenticonus) leads to an absence or diminished expression of all three chains in the GBM, further highlighting a post-translational assembly requirement between the three chains to create the unique type IV collagen network of the GBM. While recent biochemical and cell biological experiments have provided further support for inter-chain interactions between 13, 14 and 15 chains, molecular and genetic models to define the assembly of GBM type IV collagen are still lacking. Such mouse models are required for understanding the pathogenesis of Alport syndrome and developing new therapy options. In the previous funding cycle, human Alport kidneys and kidneys from mice with 13(IV) collagen deletion were used in biochemical and cell biological experiments to establish the relationship between the structure of GBM type IV collagen and its susceptibility to enhanced GBM degradation in Alport syndrome. New genetic mouse models were generated to address the specificity of type IV collagen assembly in the GBM. New cell-based therapies were tested in Alport mice and new insights into GBM repair and regeneration unraveled. In this competing renewal application, we now propose to continue our studies to understand the molecular drivers that determine the chain specific assembly of type IV collagen, specifically focusing on the 13(IV) chain and its turnover in the GBM. We will study inducible and cell-specific 13(IV) collagen deficient mice to probe turnover rate of the type IV collagen in the GBM. Additionally, new mouse models will be utilized to study the contribution of 13(IV)NC1 domain, a critical domain in 1(IV) chains, in the chain specific organization of type IV colage network in the GBM, and also evaluate the capacity of 13(IV) chain to re-assemble type IV collagen protomers in the GBM. Such studies will provide further insights into possible cell based therapy options for Alport syndrome, and will also provide a basic understanding of type IV collagen assembly in the GBM.

Public Health Relevance

Glomerular Basement Membrane (GBM) is a key component of the filtration system of the kidney glomerulus, and filters 180 liters of blood every day via about 2.5 million glomeruli. Type IV collagen is the most abundant protein present in the GBM and a key structural and functional component of the filtration system. Alport syndrome is a genetic disease associated with progressive kidney failure due to mutations in the type IV collagen. Our current proposal is designed to study the assembly of type IV collagen networks in the GBM and its role in Alport syndrome pathogenesis, and also test therapy options for this disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Ketchum, Christian J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas MD Anderson Cancer Center
United States
Zip Code
Cleland, Timothy P; Schroeter, Elena R; Zamdborg, Leonid et al. (2015) Mass Spectrometry and Antibody-Based Characterization of Blood Vessels from Brachylophosaurus canadensis. J Proteome Res 14:5252-62
Lovisa, Sara; LeBleu, Valerie S; Tampe, Björn et al. (2015) Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis. Nat Med 21:998-1009
Özdemir, Berna C; Pentcheva-Hoang, Tsvetelina; Carstens, Julienne L et al. (2014) Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25:719-34
Zeisberg, Michael; Tampe, Björn; LeBleu, Valerie et al. (2014) Thrombospondin-1 deficiency causes a shift from fibroproliferative to inflammatory kidney disease and delays onset of renal failure. Am J Pathol 184:2687-98
Kahlert, Christoph; Melo, Sonia A; Protopopov, Alexei et al. (2014) Identification of double-stranded genomic DNA spanning all chromosomes with mutated KRAS and p53 DNA in the serum exosomes of patients with pancreatic cancer. J Biol Chem 289:3869-75
Charytan, David M; Padera, Robert; Helfand, Alexander M et al. (2014) Increased concentration of circulating angiogenesis and nitric oxide inhibitors induces endothelial to mesenchymal transition and myocardial fibrosis in patients with chronic kidney disease. Int J Cardiol 176:99-109
Melo, Sonia A; Sugimoto, Hikaru; O'Connell, Joyce T et al. (2014) Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell 26:707-21
Carstens, Julienne L; Lovisa, Sara; Kalluri, Raghu (2014) Microenvironment-dependent cues trigger miRNA-regulated feedback loop to facilitate the EMT/MET switch. J Clin Invest 124:1458-60
Ayala de la Peña, Francisco; Kanasaki, Keizo; Kanasaki, Megumi et al. (2014) Specific activation of K-RasG12D allele in the bladder urothelium results in lung alveolar and vascular defects. PLoS One 9:e95888
Tampe, Björn; Tampe, Desiree; Müller, Claudia A et al. (2014) Tet3-mediated hydroxymethylation of epigenetically silenced genes contributes to bone morphogenic protein 7-induced reversal of kidney fibrosis. J Am Soc Nephrol 25:905-12

Showing the most recent 10 out of 119 publications