The main goal of this project is to investigate the structure, function and pathogenic role of a large glycoprotein called gp 330. This molecule was first identified as a major pathogenic antigen in Heymann nephritis - a rat model of human membranous glomerulonephritis. In a later study, the primary structure of gp 330, as deduced from partial cDNAs, was found to have considerable homology to the low density lipoprotein (LDL) receptor and the LDL receptor related protein (LRP), also known as the alpha2 macroglobulin receptor (alpha2MR). Recently, it has been shown that several known ligands of LRP/alpha2 MR bind to gp 330 in vitro, but the physiologic relevance of these observations is unknown, since gp 330 and LRP/alpha2MR have quite different distributions in vivo. Gp 330 is largely restricted to a group of epithelial cells whose major function appears to be absorption. A 39-44 KD protein invariably co-purifies with gp 330 and LRP/alpha2MR; this receptor associated protein (alpha2MRAP) inhibits the binding of ligands to gp 330 or LRP/alpha2MR in vitro, but its role in vivo is unknown. Major goals of this project are to obtain a full length cDNA encoding gp 330, investigate its receptor function in vivo, and to clarify the function of alpha2MRAP. In addition, the role of alpha2MRAP, gp 330 and ligands of gp 330 in the development of immune deposits in Heymann nephritis will be studied. The research may provide information about the receptor function of gp 330 and its role in specialized epithelial cells. The studies on Heymann nephritis should reveal new information about how immune deposits form in glomeruli, which is an important mechanism in major forms of human glomerulonephritis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK046301-01A1
Application #
2145482
Study Section
Pathology A Study Section (PTHA)
Project Start
1993-12-15
Project End
1997-11-30
Budget Start
1993-12-15
Budget End
1994-11-30
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Marino, M; Chiovato, L; Lisi, S et al. (2001) Binding of the low density lipoprotein receptor-associated protein (RAP) to thyroglobulin (Tg): putative role of RAP in the Tg secretory pathway. Mol Endocrinol 15:1829-37
Marino, M; Pinchera, A; McCluskey, R T et al. (2001) Megalin in thyroid physiology and pathology. Thyroid 11:47-56
Marino, M; Andrews, D; Brown, D et al. (2001) Transcytosis of retinol-binding protein across renal proximal tubule cells after megalin (gp 330)-mediated endocytosis. J Am Soc Nephrol 12:637-48
Marino, M; McCluskey, R T (2000) Role of thyroglobulin endocytic pathways in the control of thyroid hormone release. Am J Physiol Cell Physiol 279:C1295-306
Marino, M; Zheng, G; Chiovato, L et al. (2000) Role of megalin (gp330) in transcytosis of thyroglobulin by thyroid cells. A novel function in the control of thyroid hormone release. J Biol Chem 275:7125-37
Marino, M; Friedlander, J A; McCluskey, R T et al. (1999) Identification of a heparin-binding region of rat thyroglobulin involved in megalin binding. J Biol Chem 274:30377-86
Marino, M; Zheng, G; McCluskey, R T (1999) Megalin (gp330) is an endocytic receptor for thyroglobulin on cultured fisher rat thyroid cells. J Biol Chem 274:12898-904
Jung, F F; Bachinsky, D R; Tang, S S et al. (1998) Immortalized rat proximal tubule cells produce membrane bound and soluble megalin. Kidney Int 53:358-66
Hellmark, T; Niles, J L; Collins, A B et al. (1997) Comparison of anti-GBM antibodies in sera with or without ANCA. J Am Soc Nephrol 8:376-85
Abbate, M; Bachinsky, D R; McCluskey, R T et al. (1994) Expression of gp330 and gp330/alpha 2-macroglobulin receptor-associated protein in renal tubular differentiation. J Am Soc Nephrol 4:2003-15

Showing the most recent 10 out of 11 publications