Sphingolipids have historically been studied in the setting of rare genetic disorders where these compounds accumulate due to a defect in an enzyme or activator for their metabolism. However, more recent studies have identified several potential functional roles for sphingolipids, including mediators of intracellular signaling events or of cell-cell interactions. From these studies it has been proposed that sphingolipids play a role in the pathophysiology of more common disorders such as cancer or infection. We have studied the role of sphingolipids in another common disorder, diabetes mellitus, and have observed that hyperglycemia results in increased levels of renal glycosphingolipids in concert with the early hypertrophic changes of diabetic nephropathy. Hyperglycemia-induced changes in renal glycosphingolipid formation are observed in both the kidneys of streptozotocin-treated rats and in renal proximal tubule cells. Pharmacological inhibition of glucosylceramide synthesis reverses the early renal hypertrophy in diabetic kidneys and the proliferative response of proximal tubular epithelial cells cultured in hyperglycemia medium, consistent with the existence of a biochemical link between glycosphingolipids and diabetic nephropathy. We propose as the major hypothesis for this grant that the renal growth accompanying early diabetic hypertrophy is mediated by altered sphingolipid metabolism.
The specific aims of this proposal are: 1. To characterize the nature of the relationship between hyperglycemia and the rate of glycosphingolipid synthesis. 2. To define the role of individual sphingolipids in mediating the growth response to hyperglycemia. 3. To determine the role of changes in sphingolipid content in regulating IGF-1-stimulated cellular proliferation and cell cycle progression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK041487-10
Application #
2882767
Study Section
Pathology A Study Section (PTHA)
Project Start
1990-03-01
Project End
2000-02-29
Budget Start
1999-03-01
Budget End
2000-02-29
Support Year
10
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Hinkovska-Galcheva, Vania; Clark, Andrea; VanWay, Susan et al. (2008) Ceramide kinase promotes Ca2+ signaling near IgG-opsonized targets and enhances phagolysosomal fusion in COS-1 cells. J Lipid Res 49:531-42
Mansfield, Pamela J; Hinkovska-Galcheva, Vania; Borofsky, Michael S et al. (2005) Phagocytic signaling molecules in lipid rafts of COS-1 cells transfected with FcgammaRIIA. Biochem Biophys Res Commun 331:132-8
Mansfield, Pamela J; Carey, Shannon S; Hinkovska-Galcheva, Vania et al. (2004) Ceramide inhibition of phospholipase D and its relationship to RhoA and ARF1 translocation in GTP gamma S-stimulated polymorphonuclear leukocytes. Blood 103:2363-8
Mansfield, Pamela J; Hinkovska-Galcheva, Vania; Carey, Shannon S et al. (2002) Regulation of polymorphonuclear leukocyte degranulation and oxidant production by ceramide through inhibition of phospholipase D. Blood 99:1434-41
Mansfield, Pamela J; Hinkovska-Galcheva, Vania; Shayman, James A et al. (2002) Granulocyte colony-stimulating factor primes NADPH oxidase in neutrophils through translocation of cytochrome b(558) by gelatinase-granule release. J Lab Clin Med 140:9-16
Cooper, S; Shayman, J A (2001) Revisiting retinoblastoma protein phosphorylation during the mammalian cell cycle. Cell Mol Life Sci 58:580-95
Mansfield, P J; Shayman, J A; Boxer, L A (2000) Regulation of polymorphonuclear leukocyte phagocytosis by myosin light chain kinase after activation of mitogen-activated protein kinase. Blood 95:2407-12
Abe, A; Gregory, S; Lee, L et al. (2000) Reduction of globotriaosylceramide in Fabry disease mice by substrate deprivation. J Clin Invest 105:1563-71
Shu, L; Lee, L; Chang, Y et al. (2000) Caveolar structure and protein sorting are maintained in NIH 3T3 cells independent of glycosphingolipid depletion. Arch Biochem Biophys 373:83-90
Cooper, S; Yu, C; Shayman, J A (1999) Phosphorylation-dephosphorylation of retinoblastoma protein not necessary for passage through the mammalian cell division cycle. IUBMB Life 48:225-30

Showing the most recent 10 out of 38 publications