Thymic involution constitutes a hallmark of an aging immune system. The thymus is comprised of thymic epithelial cells (TECs), fibroblasts and blood-borne stromal cells. Adoptive transfers of young and old hematopoietic stem cells into young vs old recipients has led to the conclusion that impaired thymopoiesis in the aged is largely the consequence of an aged thymic microenvironment. TEC differentiation, proliferation, and survival are controlled by cell intrinsic and extrinsic factors. Although much work has been focused on thymus development during embryogenesis, comparatively little is known about the mechanisms responsible for thymic involution. This especially pertains to TECs, which we hypothesize are the major impediment to thymopoiesis during aging. We now propose to fill this critical gap.
Our specific aims are:
Aim 1 : To determine the key transcription factors &signaling pathways in TECs affected by aging.
In aim 1 A, we will interrogate physiological characteristics of aged vs young TEC subsets.
In aim 1 B, we hypothesize that key cell surface receptor and intracellular transcriptional pathways that regulate thymic development will be important for TEC maintenance and regeneration after genotoxic stress in aged mice.
In aim 1 C, we hypothesize that transcriptional regulation by micro-RNAs is an important component of TEC aging. Studies of loss-of-function in TECs alone will be performed in aims 1B and 1C.
Aim 2 : To test the hypothesis that genetic models of perturbations of the aging process will provide key insights as to the mechanisms responsible for TEC aging. We will identify common features affecting TECs between chronologically aged mice and those with premature aging and distinguishing features in a model of delayed thymic aging. As indicated, drugs that stimulate TECs as probes for assessing residual TEC function in aging.

Public Health Relevance

Our goal is to understand the causes of aged-related thymic involution and it subsequent immune deficiency. These studies, which include therapeutic interventions that are exportable into the clinic, offer the possibility of diminishing age-related complications of a poor immune system response.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG034874-04
Application #
8307330
Study Section
Special Emphasis Panel (ZAI1-BDP-I (J2))
Program Officer
Fuldner, Rebecca A
Project Start
2009-09-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$311,848
Indirect Cost
$66,338
Name
University of Minnesota Twin Cities
Department
Pediatrics
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Mirsoian, Annie; Bouchlaka, Myriam N; Sckisel, Gail D et al. (2014) Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice. J Exp Med 211:2373-83
Bouchlaka, Myriam N; Sckisel, Gail D; Chen, Mingyi et al. (2013) Aging predisposes to acute inflammatory induced pathology after tumor immunotherapy. J Exp Med 210:2223-37
Zuklys, Saulius; Mayer, Carlos E; Zhanybekova, Saule et al. (2012) MicroRNAs control the maintenance of thymic epithelia and their competence for T lineage commitment and thymocyte selection. J Immunol 189:3894-904
Lopez-Rios, Javier; Speziale, Dario; Robay, Dimitri et al. (2012) GLI3 constrains digit number by controlling both progenitor proliferation and BMP-dependent exit to chondrogenesis. Dev Cell 22:837-48
Papadopoulou, Aikaterini S; Dooley, James; Linterman, Michelle A et al. (2012) The thymic epithelial microRNA network elevates the threshold for infection-associated thymic involution via miR-29a mediated suppression of the IFN-ýý receptor. Nat Immunol 13:181-7
Taylor, Patricia A; Kelly, Ryan M; Bade, Nick D et al. (2012) FTY720 markedly increases alloengraftment but does not eliminate host anti-donor T cells that cause graft rejection on its withdrawal. Biol Blood Marrow Transplant 18:1341-52
Pedraza-Alva, Gustavo; Merida, Lilia B; del Rio, Roxana et al. (2011) CD43 regulates the threshold for T cell activation by targeting Cbl functions. IUBMB Life 63:940-8
Krenger, Werner; Blazar, Bruce R; Holländer, Georg A (2011) Thymic T-cell development in allogeneic stem cell transplantation. Blood 117:6768-76
Hollander, Georg A; Krenger, Werner; Blazar, Bruce R (2010) Emerging strategies to boost thymic function. Curr Opin Pharmacol 10:443-53
Kelly, Ryan M; Goren, Emily M; Taylor, Patricia A et al. (2010) Short-term inhibition of p53 combined with keratinocyte growth factor improves thymic epithelial cell recovery and enhances T-cell reconstitution after murine bone marrow transplantation. Blood 115:1088-97