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Serpina1b  -  serine (or cysteine) preptidase inhibitor,...

Mus musculus

Synonyms: AAT, Aat2, Alpha-1 protease inhibitor 2, Alpha-1-antiproteinase, Alpha-1-antitrypsin 1-2, ...
 
 
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Disease relevance of Serpina1b

  • Transiently expressed mutant and WT AAT variants underwent rapid destabilization in response to an artificially elevated ERManI concentration in the murine hepatoma cell line, Hepa1a [1].
  • Phase I trial of intramuscular injection of a recombinant adeno-associated virus alpha 1-antitrypsin (rAAV2-CB-hAAT) gene vector to AAT-deficient adults [2].
  • Optimal therapy for AAT deficiency will require a high percentage of hepatocyte transduction to be effective for liver and lung disease [3].
  • A single injection of an EBV/genomic SERPINA1 vector provided >300 microg/ml of AAT, which approached normal plasma levels and persisted for the >9-month duration of the experiment [4].
 

High impact information on Serpina1b

  • Using peritoneal infiltration models, we demonstrate that AAT decreases allogeneic fibroblast-elicited natural-killer-cell influx by 89%, CD3-positive cell influx by 44%, and thioglycolate-elicited neutrophil emigration by 66% [5].
  • For newly synthesized alpha1-antitrypsin (AAT), the modification of its asparagine-linked oligosaccharides by a slow-acting mannosidase partitions the misfolded monomer into the proteasomal degradation pathway [1].
  • Herein, we asked whether, and how, modification by endoplasmic reticulum mannosidase I (ERManI) contributes to the preferential selection of the misfolded AAT monomer for proteasomal degradation [1].
  • In addition, staining of endothelial cells with ATZ11 antibody in both M- and Z-AAT individuals shows that AAT attached to endothelial cells is in a polymerized form [6].
  • T cell receptor spectratyping indicated that AAT gene therapy altered T cell repertoire diversity in splenocytes from NOD mice [7].
 

Biological context of Serpina1b

  • Adoptive transfer experiments demonstrated that AAT gene therapy attenuated cellular immunity associated with beta cell destruction [7].
  • Safety parameters will be measurement of changes in serum chemistries and hematology, urinalysis, pulmonary function testing, semen assay for vector genomes, immunologic response to AAT, and AAV, as well as reported subject history of any symptoms [2].
  • This study demonstrates that AAT gene therapy attenuates cell-mediated autoimmunity, alters the T cell receptor repertoire, and efficiently prevents type 1 diabetes in the NOD mouse model [7].
  • The pTG7101 plasmid, containing the full-length human AAT gene, was encapsulated in small liposomes bearing 10% of negatively (phosphatidylserine, PS) or positively (DOTAP) charged lipids [8].
  • Neither the PI2 nor the I1 spots were centromere associated, nor could they be correlated with specific interchromatinic structures in conventional preparations and in unlabelled controls [9].
 

Anatomical context of Serpina1b

  • Retinoic acid does not affect the angiogenic capacity of the VYS mesenchyme but destroys lysosomes, which release hydrolytic enzymes, leading to degradation of AAT in the endodermal cells and then digestion of endocytosed bFGF [10].
  • Thin sections of mouse 3T3 fibroblast nuclei labelled by immunoperoxidase with anti-nuclear antibodies I1, PI1, PI2, anti-peripherin, -lamin, and -centromere have been examined in the electron microscope [9].
  • The peripheral components of PI1 and PI2 appear to be localized at nuclear pores and the nuclear envelope, respectively [9].
  • Therefore, pseudotyped AAV8 provides a vehicle to infect a high percentage of hepatocytes stably and thereby express therapeutic molecules to modify AAT PiZ transcripts [3].
  • Osteoblast and bone final concentrates comigrated with Trasylol but were electrophoretically distinct from alpha 1-antiproteinase [11].
 

Other interactions of Serpina1b

  • Whereas peripherin and PI2 antigens did not reorganize during stimulation, labelling of PI1 and small nuclear ribonucleoprotein (snRNP) antigens increased markedly in intensity and redistributed in concert with the previously reported NM restructuring [12].
 

Analytical, diagnostic and therapeutic context of Serpina1b

  • In light of the established safety record and the nondiabetogenic potential of AAT, these data suggest that AAT may be beneficial as adjunctive therapy in patients undergoing islet transplantation [5].
  • Using electrophoresis, Western blotting, and ELISA procedures, we have shown in the present study that this monoclonal antibody specifically detects a conformation-dependent neoepitope on both polymerized and elastase-complexed molecular forms of AAT [6].
  • These results strongly suggest that rAAV1-mediated AAT gene therapy may be useful as a novel approach to prevent type 1 diabetes [7].
  • The efficiency of both anionic and cationic liposomes as vectors for in vivo human alpha1-antitrypsin (AAT) gene transfer was studied in mice with and without an associated partial hepatectomy [8].

References

  1. Elucidation of the molecular logic by which misfolded alpha 1-antitrypsin is preferentially selected for degradation. Wu, Y., Swulius, M.T., Moremen, K.W., Sifers, R.N. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  2. Phase I trial of intramuscular injection of a recombinant adeno-associated virus alpha 1-antitrypsin (rAAV2-CB-hAAT) gene vector to AAT-deficient adults. Flotte, T.R., Brantly, M.L., Spencer, L.T., Byrne, B.J., Spencer, C.T., Baker, D.J., Humphries, M. Hum. Gene Ther. (2004) [Pubmed]
  3. Efficient hepatic delivery and expression from a recombinant adeno-associated virus 8 pseudotyped alpha1-antitrypsin vector. Conlon, T.J., Cossette, T., Erger, K., Choi, Y.K., Clarke, T., Scott-Jorgensen, M., Song, S., Campbell-Thompson, M., Crawford, J., Flotte, T.R. Mol. Ther. (2005) [Pubmed]
  4. Epstein-Barr virus/human vector provides high-level, long-term expression of alpha1-antitrypsin in mice. Stoll, S.M., Sclimenti, C.R., Baba, E.J., Meuse, L., Kay, M.A., Calos, M.P. Mol. Ther. (2001) [Pubmed]
  5. Alpha1-antitrypsin monotherapy prolongs islet allograft survival in mice. Lewis, E.C., Shapiro, L., Bowers, O.J., Dinarello, C.A. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  6. Detection of circulating and endothelial cell polymers of Z and wild type alpha 1-antitrypsin by a monoclonal antibody. Janciauskiene, S., Dominaitiene, R., Sternby, N.H., Piitulainen, E., Eriksson, S. J. Biol. Chem. (2002) [Pubmed]
  7. Alpha1-antitrypsin gene therapy modulates cellular immunity and efficiently prevents type 1 diabetes in nonobese diabetic mice. Lu, Y., Tang, M., Wasserfall, C., Kou, Z., Campbell-Thompson, M., Gardemann, T., Crawford, J., Atkinson, M., Song, S. Hum. Gene Ther. (2006) [Pubmed]
  8. Long-term expression of the human alpha1-antitrypsin gene in mice employing anionic and cationic liposome vectors. Crepso, J., Blaya, C., Crespo, A., Aliño, S.F. Biochem. Pharmacol. (1996) [Pubmed]
  9. Ultrastructural localization of nuclear antigens during interphase in mouse 3T3 fibroblasts. Chaly, N., St Aubin, G., Brown, D.L. Biochem. Cell Biol. (1989) [Pubmed]
  10. Induction of avascular yolk sac due to reduction of basic fibroblast growth factor by retinoic acid in mice. Yasuda, Y., Nishi, N., Takahashi, J.A., Konishi, H., Ohara, I., Fujita, H., Ohta, M., Itoh, N., Hatanaka, M., Tanimura, T. Dev. Biol. (1992) [Pubmed]
  11. Osteoblast low-molecular-weight proteinase inhibitor. I. Isolation and characterization of activity from osteoblastic cells and bone. Wezeman, F.H., Corey, J., Waxler, B. Calcif. Tissue Int. (1990) [Pubmed]
  12. Modulation of lymphocyte nuclear matrix organization in vivo by 5,6-dichloro-1-beta-D-ribofuranosyl benzimidazole: an autoradiographic and immunofluorescence study. Chaly, N., Cadrin, M., Kaplan, J.G., Brown, D.L. Biol. Cell (1988) [Pubmed]
 
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