We have developed a line of mice bearing a targeted mutation in the TATA-binding protein (TBP) that replaces the endogenous gene with a version that is identical except it produces a protein lacking 111 of the first 135 amino acids of the protein. Adult mice homozygous for this mutation (tbp ^N/^N are normal;however mutant fetuses suffer a very high rate of immune-mediated mid gestational miscarriages. We can rescue the mutants past this crisis in various ways, including: 1) providing them with wildtype extra embryonic tissues;2) rearing them in severely immune compromised dams;or 3) disrupting fetal (2m expression in their placentas. Thus, these mice provide an important model system for studying both the fetal and the maternal side of the maternal/fetal immune interaction. We hypothesize that the maternal/fetal immune interaction involves the interplay between maternal immune cells and fetal genes expressed at the maternal/fetal interface in the placenta;alteration of either maternal or fetal players in this interaction can affect the outcome of pregnancy. In this study, we propose three Specific Aims:
Aim 1, identify the cellular components of the maternal immune system that participate in rejection of tbp^N/^N fetuses;
Aim 2, characterize expression of MHC-I family genes at the implantation sites of tbp+/+, tbp^N/+, and tbp^N/^N fetuses;
and Aim 3, identify proteins that interact with the TBP N-terminus in placenta. Results obtained under Specific Aim 1 should reveal maternal factors that can compromise pregnancy. Results obtained under Specific Aim 2 are expected to reveal fetal gene expression defects that might compromise pregnancy. Discoveries made under Aims 1 and 2 could lead to novel therapeutic strategies for combating chronic miscarriages. Finally, results obtained under Specific Aim 3 are expected to reveal gene regulatory mechanisms that underlie expression defects which can compromise pregnancy. These results could lead to novel prognostic tools for predicting susceptibility to spontaneous miscarriages.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI055739-05
Application #
7557850
Study Section
Cellular and Molecular Immunology - B (CMI)
Program Officer
Prabhudas, Mercy R
Project Start
2005-02-01
Project End
2011-01-31
Budget Start
2009-02-01
Budget End
2011-01-31
Support Year
5
Fiscal Year
2009
Total Cost
$324,028
Indirect Cost
Name
Montana State University - Bozeman
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
625447982
City
Bozeman
State
MT
Country
United States
Zip Code
59717
Prigge, Justin R; Coppo, Lucia; Martin, Sebastin S et al. (2017) Hepatocyte Hyperproliferation upon Liver-Specific Co-disruption of Thioredoxin-1, Thioredoxin Reductase-1, and Glutathione Reductase. Cell Rep 19:2771-2781
Kim, Junhwan; Fujioka, Hisashi; Oleinick, Nancy L et al. (2010) Photosensitization of intact heart mitochondria by the phthalocyanine Pc 4: Correlation of structural and functional deficits with cytochrome c release. Free Radic Biol Med 49:726-32
Kim, Junhwan; Rodriguez, Myriam E; Oleinick, Nancy L et al. (2010) Photo-oxidation of cardiolipin and cytochrome c with bilayer-embedded Pc 4. Free Radic Biol Med 49:718-25
Prigge, Justin R; Iverson, Sonya V; Siders, Ashley M et al. (2009) Interactome for auxiliary splicing factor U2AF(65) suggests diverse roles. Biochim Biophys Acta 1789:487-92
Weisend, Carla M; Kundert, Jean A; Suvorova, Elena S et al. (2009) Cre activity in fetal albCre mouse hepatocytes: Utility for developmental studies. Genesis 47:789-92
Kundert, Jean A; Sealey, Amy L; Li, Yan et al. (2008) Syngeneic immune-dependent abortions in mice suggest paternal alloantigen-independent mechanisms. Am J Reprod Immunol 60:290-7
Kim, Junhwan; Rodriguez, Myriam E; Guo, Ming et al. (2008) Oxidative modification of cytochrome c by singlet oxygen. Free Radic Biol Med 44:1700-11
Bondareva, Alla A; Capecchi, Mario R; Iverson, Sonya V et al. (2007) Effects of thioredoxin reductase-1 deletion on embryogenesis and transcriptome. Free Radic Biol Med 43:911-23
Schmidt, Edward E; Davies, Christopher J (2007) The origins of polypeptide domains. Bioessays 29:262-70
Prigge, Justin R; Schmidt, Edward E (2007) HAP1 can sequester a subset of TBP in cytoplasmic inclusions via specific interaction with the conserved TBP(CORE). BMC Mol Biol 8:76

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