The objective of the proposed research is to describe in molecular terms how immunoglobulins are transported from a pregnant or nursing mammal to her unborn or newborn offspring. The acquisition of maternal antibodies is essential for immunologic defense, although autoantibodies and immune complexes of live pathogens are potentially harmful to the neonate. We have two major goals. The first is to elucidate the molecular mechanism of intestinal IgG uptake in the suckling rat by an Fc receptor called FcRn (for neonate). This system will be used as a model for intracellular protein trafficking and specifically for the transmission of IgG across the human placenta. To identify and characterized charcterize the Fc receptor(s) that mediate placental transport of IgG is our second goal.
Our specific aims are to: 1. Develop a monolayer cell culture model for transcytosis of IgG by FcRn. 2. Relate the structure of FcRn to its functions by measuring the properties of modified forms of the receptor in the cell culture model. 3. Study how the gene(s) that code for FcRn is (are) organized. 4. Study how the production of FcRn is regulated during development. 5. Identify and characterize by molecular cloning FcRs that transport IgG across human placenta.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD027691-04
Application #
2200569
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1991-02-01
Project End
1995-07-31
Budget Start
1994-02-01
Budget End
1995-07-31
Support Year
4
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Brandeis University
Department
Type
Organized Research Units
DUNS #
616845814
City
Waltham
State
MA
Country
United States
Zip Code
02454
Newton, Estelle E; Wu, Zhen; Simister, Neil E (2005) Characterization of basolateral-targeting signals in the neonatal Fc receptor. J Cell Sci 118:2461-9
Wernick, Naomi L B; Haucke, Volker; Simister, Neil E (2005) Recognition of the tryptophan-based endocytosis signal in the neonatal Fc Receptor by the mu subunit of adaptor protein-2. J Biol Chem 280:7309-16
Simister, Neil E (2003) Placental transport of immunoglobulin G. Vaccine 21:3365-9
McCarthy, K M; Lam, M; Subramanian, L et al. (2001) Effects of mutations in potential phosphorylation sites on transcytosis of FcRn. J Cell Sci 114:1591-8
Wu, Z; Simister, N E (2001) Tryptophan- and dileucine-based endocytosis signals in the neonatal Fc receptor. J Biol Chem 276:5240-7
McCarthy, K M; Yoong, Y; Simister, N E (2000) Bidirectional transcytosis of IgG by the rat neonatal Fc receptor expressed in a rat kidney cell line: a system to study protein transport across epithelia. J Cell Sci 113 ( Pt 7):1277-85
Kacskovics, I; Wu, Z; Simister, N E et al. (2000) Cloning and characterization of the bovine MHC class I-like Fc receptor. J Immunol 164:1889-97
Mikulska, J E; Pablo, L; Canel, J et al. (2000) Cloning and analysis of the gene encoding the human neonatal Fc receptor. Eur J Immunogenet 27:231-40
Mikulska, J E; Simister, N E (2000) Analysis of the promoter region of the human FcRn gene. Biochim Biophys Acta 1492:180-4
Dickinson, B L; Badizadegan, K; Wu, Z et al. (1999) Bidirectional FcRn-dependent IgG transport in a polarized human intestinal epithelial cell line. J Clin Invest 104:903-11

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