Abstract

The overall aim of this project is to identify genes, primarily through genome-wide RNAi screens and cDNA library over-expression, that can act as potential drug targets to promote the survival of organisms irradiated with a dose of irradiation capable of destroying their hematopoetic system. We will probe different aspects of survival in response to IR including direct survival, resistance to oxidative stress, the control of hematopoetic stem cell proliferation and differentiation, and apoptosis control. We will also screen for chemicals that disrupt the major known checkpoint pathway known to cause killing in response to IR and for inhibitors of proteins identified in our RNAi screens, in order to identify molecules that can prolong survival after exposure to ionizing radiation. We will investigate the pathways involved in radio-resistance genetically and chemically with the goal of finding drugs and drug targets that will promote survival of people who have undergone potentially lethal irradiation.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI067751-01
Application #
7054545
Study Section
Special Emphasis Panel (ZCA1-SRRB-E (O1))
Project Start
2005-09-01
Project End
2010-07-31
Budget Start
2005-09-01
Budget End
2006-07-31
Support Year
1
Fiscal Year
2005
Total Cost
$466,400
Indirect Cost

  Institution

Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215

  Publications

Beemelmanns, Christine; Ramadhar, Timothy R; Kim, Ki Hyun et al. (2017) Macrotermycins A-D, Glycosylated Macrolactams from a Termite-Associated Amycolatopsis sp. M39. Org Lett 19:1000-1003
Guinan, Eva C; Palmer, Christine D; Mancuso, Christy J et al. (2014) Identification of single nucleotide polymorphisms in hematopoietic cell transplant patients affecting early recognition of, and response to, endotoxin. Innate Immun 20:697-711
Guinan, Eva C; Barbon, Christine M; Kalish, Leslie A et al. (2011) Bactericidal/permeability-increasing protein (rBPI21) and fluoroquinolone mitigate radiation-induced bone marrow aplasia and death. Sci Transl Med 3:110ra118
D'Andrea, Alan D (2010) Susceptibility pathways in Fanconi's anemia and breast cancer. N Engl J Med 362:1909-19
Parmar, Kalindi; Kim, Jungmin; Sykes, Stephen M et al. (2010) Hematopoietic stem cell defects in mice with deficiency of Fancd2 or Usp1. Stem Cells 28:1186-95
Tolopko, Andrew N; Sullivan, John P; Erickson, Sean D et al. (2010) Screensaver: an open source lab information management system (LIMS) for high throughput screening facilities. BMC Bioinformatics 11:260
Parmar, Kalindi; D'Andrea, Alan; Niedernhofer, Laura J (2009) Mouse models of Fanconi anemia. Mutat Res 668:133-40
Sun, Yingli; Jiang, Xiaofeng; Xu, Ye et al. (2009) Histone H3 methylation links DNA damage detection to activation of the tumour suppressor Tip60. Nat Cell Biol 11:1376-82
Moldovan, George-Lucian; D'Andrea, Alan D (2009) FANCD2 hurdles the DNA interstrand crosslink. Cell 139:1222-4
Kim, Jung Min; Parmar, Kalindi; Huang, Min et al. (2009) Inactivation of murine Usp1 results in genomic instability and a Fanconi anemia phenotype. Dev Cell 16:314-20

Showing the most recent 10 out of 19 publications