Cubilin is a peripheral membrane protein that works in conjunction with its co-receptor megalin to mediate endocytosis of high density lipoproteins (HDL) in the yolk sac visceral endoderm (VE) and in renal proximal tubules. The significance of cubilin mediated HDL uptake to embryonic development as well as adult physiology is not known. During development, it is hypothesized that cubilin activity is essential for embryonic acquisition of maternal HDL-associated cholesterol, phospholipids, triglycerides and/or lipid soluble vitamins required to support embryogenesis. The vital role served by yolk sac cubilin is indicated by the severe developmental abnormalities observed when cubilin antibodies are administered to pregnant rats or to embryos cultured ex utero. In adult physiology, it is hypothesized that renal cubilin/megalin uptake of HDL is involved in a feedback mechanism that influences steady state levels of HDL in the blood. Support for this hypothesis comes from our findings that conditional deficiency of renal megalin activity causes an increase in plasma HDL. To test the above hypotheses, and to characterize fundamental mechanistic features of cubilin function, three specific aims are proposed.
The first aim i s to characterize the developmental and physiological abnormalities that arise in mice homozygous and heterozygous for targeted deletion of the cubilin gene. Emphasis will be placed on determining of the impact of cubilin deficiency on HDL metabolism. For use in these studies we have developed a novel mouse model of cubilin deficiency. There is also a plan to develop a conditional knockout model to characterize the renal-specific functions of cubilin.
The second aim i s to determine the significance of each of the three known cubilin co-receptors, megalin, amnionless (AMN) and the cation-independent mannose 6-phosphate/insulin-like growth factor ll-receptor (CIMPR), to the process of embryonic uptake of maternal HDL. These studies will include evaluation of yolk sac endodermal trafficking of HDL to determine whether it is targeted to lysosomes or transported across the VE via transcytosis.
The third aim i s to define the molecular basis for ligand binding and endocytotic functions of cubilin with the primary objectives being to map binding sites within cubilin for HDL, apolipoprotein A-l and the co-receptors. Together, these studies will provide new insights into the function of cubilin in maternal-embryonic.lipoprotein transport, embryonic development and adult kidney function. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061873-06
Application #
7292750
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Ershow, Abby
Project Start
2000-04-01
Project End
2010-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
6
Fiscal Year
2007
Total Cost
$354,415
Indirect Cost
Name
Medical University of South Carolina
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Aseem, Obaidullah; Smith, Brian T; Cooley, Marion A et al. (2014) Cubilin maintains blood levels of HDL and albumin. J Am Soc Nephrol 25:1028-36
Aseem, Obaidullah; Barth, Jeremy L; Klatt, Sandra C et al. (2013) Cubilin expression is monoallelic and epigenetically augmented via PPARs. BMC Genomics 14:405
Wilkerson, Brent A; Grass, G Daniel; Wing, Shane B et al. (2012) Sphingosine 1-phosphate (S1P) carrier-dependent regulation of endothelial barrier: high density lipoprotein (HDL)-S1P prolongs endothelial barrier enhancement as compared with albumin-S1P via effects on levels, trafficking, and signaling of S1P1. J Biol Chem 287:44645-53
Fleming, Paul A; Argraves, W Scott; Gentile, Carmine et al. (2010) Fusion of uniluminal vascular spheroids: a model for assembly of blood vessels. Dev Dyn 239:398-406
Argraves, Kelley M; Wilkerson, Brent A; Argraves, W Scott (2010) Sphingosine-1-phosphate signaling in vasculogenesis and angiogenesis. World J Biol Chem 1:291-7
Hammad, Samar M; Twal, Waleed O; Barth, Jeremy L et al. (2009) Oxidized LDL immune complexes and oxidized LDL differentially affect the expression of genes involved with inflammation and survival in human U937 monocytic cells. Atherosclerosis 202:394-404
Morales, Carlos R; Marat, Andrea L; Ni, Xiaoyan et al. (2008) ATP-binding cassette transporters ABCA1, ABCA7, and ABCG1 in mouse spermatozoa. Biochem Biophys Res Commun 376:472-7
Gentile, Carmine; Fleming, Paul A; Mironov, Vladimir et al. (2008) VEGF-mediated fusion in the generation of uniluminal vascular spheroids. Dev Dyn 237:2918-25
Kern, Christine B; Norris, Russell A; Thompson, Robert P et al. (2007) Versican proteolysis mediates myocardial regression during outflow tract development. Dev Dyn 236:671-83
Drake, Christopher J; Fleming, Paul A; Argraves, W Scott (2007) The genetics of vasculogenesis. Novartis Found Symp 283:61-71;discussion 71-6, 238-41

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