Abstract

The proposed studies are aimed at the elucidation of mechanisms that control precursor lymphocyte differentiation with a particular focus on factors that regulate antigen receptor variable region gene assembly (VDJ recombination). Cloned VDJ recombination substrates will be introduced into transgenic or chimeric animals to elucidate elements that control stage and lineage-specificity of VDJ recombinase activity within the lymphoid lineages. Other types of VDJ recombination substrates will be transfected into VDJ recombinase-positive cell lines to study molecular details of how particular elements defined in transgenic assays influence accessibility of substrate gene segments to VDJ recombinase. A particular focus of the latter studies will be to generate novel pre-B lines that provide a more physiologically representative system for these assays. Novel cellular and animals models will be generated to study factors involved with the progression of cells through the precursor stages of the B cell differentiation pathway. Animal models will include mice unable to assemble endogenous immunoglobulin heavy chain genes and mice that constitutively express VDJ recombination enzymes throughout B cell differentiation; these systems will permit elucidation of the function and control of ordered assembly of immunoglobulin heavy and light chain genes and help elucidate the function and regulation of allelic exclusion.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI020047-17
Application #
2886438
Study Section
Special Emphasis Panel (NSS)
Program Officer
Kerr, Lawrence D
Project Start
1983-04-01
Project End
2001-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
17
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Immune Disease Institute, Inc.
Department
Type
DUNS #
115524410
City
Boston
State
MA
Country
United States
Zip Code
02115

  Publications

Zhao, Lijuan; Frock, Richard L; Du, Zhou et al. (2016) Orientation-specific RAG activity in chromosomal loop domains contributes to Tcrd V(D)J recombination during T cell development. J Exp Med 213:1921-36
Tian, Ming; Cheng, Cheng; Chen, Xuejun et al. (2016) Induction of HIV Neutralizing Antibody Lineages in Mice with Diverse Precursor Repertoires. Cell 166:1471-1484.e18
Hu, Jiazhi; Zhang, Yu; Zhao, Lijuan et al. (2015) Chromosomal Loop Domains Direct the Recombination of Antigen Receptor Genes. Cell 163:947-59
Wesemann, Duane R; Portuguese, Andrew J; Meyers, Robin M et al. (2013) Microbial colonization influences early B-lineage development in the gut lamina propria. Nature 501:112-5
Wesemann, Duane R; Portuguese, Andrew J; Magee, Jennifer M et al. (2012) Reprogramming IgH isotype-switched B cells to functional-grade induced pluripotent stem cells. Proc Natl Acad Sci U S A 109:13745-50
Subrahmanyam, Ramesh; Du, Hansen; Ivanova, Irina et al. (2012) Localized epigenetic changes induced by DH recombination restricts recombinase to DJH junctions. Nat Immunol 13:1205-12
Zha, Shan; Guo, Chunguang; Boboila, Cristian et al. (2011) ATM damage response and XLF repair factor are functionally redundant in joining DNA breaks. Nature 469:250-4
Giallourakis, Cosmas C; Franklin, Andrew; Guo, Chunguang et al. (2010) Elements between the IgH variable (V) and diversity (D) clusters influence antisense transcription and lineage-specific V(D)J recombination. Proc Natl Acad Sci U S A 107:22207-12
Lee, Yu Nee; Alt, Frederick W; Reyes, Julia et al. (2009) Differential utilization of T cell receptor TCR alpha/TCR delta locus variable region gene segments is mediated by accessibility. Proc Natl Acad Sci U S A 106:17487-92
Carpenter, Andrea C; Yang-Iott, Katherine S; Chao, Linda H et al. (2009) Assembled DJ beta complexes influence TCR beta chain selection and peripheral V beta repertoire. J Immunol 182:5586-95

Showing the most recent 10 out of 138 publications