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Genomic deletion of GIT2 induces a premature age-related thymic dysfunction and systemic immune system disruption.

dc.contributor.author Siddiqui, S
dc.contributor.author Lustig, A
dc.contributor.author Carter, A
dc.contributor.author Sankar, M
dc.contributor.author Daimon, CM
dc.contributor.author Premont, Richard Thomas
dc.contributor.author Etienne, H
dc.contributor.author van Gastel, J
dc.contributor.author Azmi, A
dc.contributor.author Janssens, J
dc.contributor.author Becker, KG
dc.contributor.author Zhang, Y
dc.contributor.author Wood, W
dc.contributor.author Lehrmann, E
dc.contributor.author Martin, JG
dc.contributor.author Martin, B
dc.contributor.author Taub, DD
dc.contributor.author Maudsley, S
dc.coverage.spatial United States
dc.date.accessioned 2017-05-01T13:33:10Z
dc.date.available 2017-05-01T13:33:10Z
dc.date.issued 2017-03-04
dc.identifier https://www.ncbi.nlm.nih.gov/pubmed/28260693
dc.identifier 101185
dc.identifier.uri https://hdl.handle.net/10161/14223
dc.description.abstract Recent research has proposed that GIT2 (G protein-coupled receptor kinase interacting protein 2) acts as an integrator of the aging process through regulation of 'neurometabolic' integrity. One of the commonly accepted hallmarks of the aging process is thymic involution. At a relatively young age, 12 months old, GIT2(-/-) mice present a prematurely distorted thymic structure and dysfunction compared to age-matched 12 month-old wild-type control (C57BL/6) mice. Disruption of thymic structure in GIT2(-/-) (GIT2KO) mice was associated with a significant reduction in the expression of the cortical thymic marker, Troma-I (cytokeratin 8). Double positive (CD4(+)CD8(+)) and single positive CD4(+) T cells were also markedly reduced in 12 month-old GIT2KO mice compared to age-matched control wild-type mice. Coincident with this premature thymic disruption in GIT2KO mice was the unique generation of a novel cervical 'organ', i.e. 'parathymic lobes'. These novel organs did not exhibit classical peripheral lymph node-like characteristics but expressed high levels of T cell progenitors that were reflexively reduced in GIT2KO thymi. Using signaling pathway analysis of GIT2KO thymus and parathymic lobe transcriptomic data we found that the molecular signaling functions lost in the dysfunctional GIT2KO thymus were selectively reinstated in the novel parathymic lobe - suggestive of a compensatory effect for the premature thymic disruption. Broader inspection of high-dimensionality transcriptomic data from GIT2KO lymph nodes, spleen, thymus and parathymic lobes revealed a systemic alteration of multiple proteins (Dbp, Tef, Per1, Per2, Fbxl3, Ddit4, Sin3a) involved in the multidimensional control of cell cycle clock regulation, cell senescence, cellular metabolism and DNA damage. Altered cell clock regulation across both immune and non-immune tissues therefore may be responsible for the premature 'aging' phenotype of GIT2KO mice.
dc.language eng
dc.relation.ispartof Aging (Albany NY)
dc.relation.isversionof 10.18632/aging.101185
dc.subject CXCR4
dc.subject GIT2
dc.subject T cell differentiation
dc.subject aging
dc.subject bioinformatics
dc.subject clock
dc.subject metabolism
dc.subject thymic involution
dc.title Genomic deletion of GIT2 induces a premature age-related thymic dysfunction and systemic immune system disruption.
dc.type Journal article
pubs.author-url https://www.ncbi.nlm.nih.gov/pubmed/28260693
pubs.begin-page 706
pubs.end-page 740
pubs.issue 3
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Duke
pubs.organisational-group Duke Institute for Brain Sciences
pubs.organisational-group Institutes and Provost's Academic Units
pubs.organisational-group Medicine
pubs.organisational-group Medicine, Gastroenterology
pubs.organisational-group School of Medicine
pubs.organisational-group University Institutes and Centers
pubs.publication-status Published
pubs.volume 9
dc.identifier.eissn 1945-4589


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