Abstract

Hematopoietic stem cell (HSC) transplantation (HSCT) is an effective treatment for patients with blood disorders or after radiation injury from a nuclear accident or terrorist attack. Total body irradiation (TBI) has been an indispensable component in a variety of host conditioning regimens for HSCT. However, it is known that ionizing radiation exerts """"""""bystander effects"""""""" on non-targeted cells and that transplanted HSCs suffer from proliferative exhaustion in irradiated recipients. Moreover, our own preliminary study documented a negative proliferation-independent bystander effect of the TBI- conditioned mouse recipients on transplanted HSCs. Therefore, efficacy of HSCT is determined by not only donor HSCs but also host conditions. In this application, we plan to: 1) further quantify the negative bystander effects of irradiated bone marrow on transplanted HSCs at different time points upon transplantation in the hosts that will be conditioned with different doses of gamma irradiation;2) then examine specific cellular and molecular mechanisms underlying the negative effect;and 3) finally explore the beneficial effects of several anti-oxidative agents in HSCT. Results from our current proposed study will yield novel strategies for enhancing the engraftment efficiency of transplanted HSCs in irradiated recipients. Abstract: Hematopoietic stem cell (HSC) transplantation (HSCT) is an effective treatment for patients with blood disorders or after radiation injury from a nuclear accident or terrorist attack. In this study, we are going to study how irradiated hosts may negatively impact the transplanted HSCs. Results from our proposed studies will yield novel strategies for enhancing the engraftment efficiency of transplanted HSCs in irradiated recipients.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI080424-05
Application #
8288778
Study Section
Special Emphasis Panel (ZAI1-TP-I (M1))
Program Officer
Dicarlo-Cohen, Andrea L
Project Start
2008-07-01
Project End
2013-12-30
Budget Start
2012-07-01
Budget End
2013-12-30
Support Year
5
Fiscal Year
2012
Total Cost
$371,213
Indirect Cost
$126,188

  Institution

Name
University of Pittsburgh
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213

  Publications

Leibowitz, Brian J; Wei, Liang; Zhang, Lin et al. (2014) Ionizing irradiation induces acute haematopoietic syndrome and gastrointestinal syndrome independently in mice. Nat Commun 5:3494
Li, Yanxin; Feng, Haizhong; Gu, Haihui et al. (2013) The p53-PUMA axis suppresses iPSC generation. Nat Commun 4:2174
Miao, Weimin; Xufeng, Richard; Park, Moo-Rim et al. (2013) Hematopoietic stem cell regeneration enhanced by ectopic expression of ROS-detoxifying enzymes in transplant mice. Mol Ther 21:423-32
Shen, Hongmei; Yu, Hui; Liang, Paulina H et al. (2012) An acute negative bystander effect of ýý-irradiated recipients on transplanted hematopoietic stem cells. Blood 119:3629-37
Leibowitz, Brian J; Qiu, Wei; Liu, Hongtao et al. (2011) Uncoupling p53 functions in radiation-induced intestinal damage via PUMA and p21. Mol Cancer Res 9:616-25
Shen, Hongmei; Yu, Hui; Liang, Paulina H et al. (2011) Bid is a positive regulator for donor-derived lymphoid cell regeneration in ýý-irradiated recipients. Exp Hematol 39:947-957.e1
Cho, Joonseok; Shen, Hongmei; Yu, Hui et al. (2011) Ewing sarcoma gene Ews regulates hematopoietic stem cell senescence. Blood 117:1156-66
Song, Y; Bahnson, A; Hall, N et al. (2010) Stem cell traits in long-term co-culture revealed by time-lapse imaging. Leukemia 24:153-61
Yu, Hui; Shen, Hongmei; Yuan, Youzhong et al. (2010) Deletion of Puma protects hematopoietic stem cells and confers long-term survival in response to high-dose gamma-irradiation. Blood 115:3472-80
XuFeng, Richard; Boyer, Matthew J; Shen, Hongmei et al. (2009) ADAR1 is required for hematopoietic progenitor cell survival via RNA editing. Proc Natl Acad Sci U S A 106:17763-8

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