Abstract

Ionizing irradiation induces RNAs in cells which can be targeted prior to irradiation by siRNA to identify novel targets for radioprotector drugs. We have successfully used this strategy to identify a co,mmon drug, Glyburide, as a novel radioprotector. We now propose to apply this strategy to identify radiation mitigator drugs using radiosensitive human cell targets and siRNA screening after irradiation. The 1** Specific Aim will optimize and deploy sentinel cells for detecting RNA targets for new mitigator drugs.
The second aim will be to use druggable siRNA libraries and small molecule libraries to identify radiation damage mitigators.
The third aim will be to identify targets that interact positively with prioritized drugs to advance radiation mitigation effects.

Public Health Relevance

We have successfully proven that siRNA library screening can be used to identify radioprotector drugs among commonly available pharmacologic agents. This same strategy will identify mitigator drugs that may be available in the existing pharmacopea and their interaction with prioritized compounds developed already in the CMCR..

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI068021-08
Application #
8382544
Study Section
Special Emphasis Panel (ZAI1-KS-I)
Project Start
Project End
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
8
Fiscal Year
2012
Total Cost
$395,776
Indirect Cost
$119,375

  Institution

Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213

  Publications

Willis, John; Epperly, Michael W; Fisher, Renee et al. (2018) Amelioration of Head and Neck Radiation-Induced Mucositis and Distant Marrow Suppression in Fanca-/- and Fancg-/- Mice by Intraoral Administration of GS-Nitroxide (JP4-039). Radiat Res 189:560-578
Leibowitz, Brian J; Yang, Liheng; Wei, Liang et al. (2018) Targeting p53-dependent stem cell loss for intestinal chemoprotection. Sci Transl Med 10:
Knickelbein, Kyle; Tong, Jingshan; Chen, Dongshi et al. (2018) Restoring PUMA induction overcomes KRAS-mediated resistance to anti-EGFR antibodies in colorectal cancer. Oncogene 37:4599-4610
Wei, Liang; Leibowitz, Brian J; Epperly, Michael et al. (2018) The GS-nitroxide JP4-039 improves intestinal barrier and stem cell recovery in irradiated mice. Sci Rep 8:2072
Christner, Susan; Guo, Jianxia; Parise, Robert A et al. (2018) Liquid chromatography-tandem mass spectrometric assay for the quantitation of the novel radiation protective agent and radiation mitigator JP4-039 in murine plasma. J Pharm Biomed Anal 150:169-175
Wang, Yi-Jun; Fletcher, Rochelle; Yu, Jian et al. (2018) Immunogenic effects of chemotherapy-induced tumor cell death. Genes Dis 5:194-203
Chen, Dongshi; Tong, Jingshan; Yang, Liheng et al. (2018) PUMA amplifies necroptosis signaling by activating cytosolic DNA sensors. Proc Natl Acad Sci U S A 115:3930-3935
Chen, Dongshi; Ni, Hong-Min; Wang, Lei et al. (2018) PUMA induction mediates acetaminophen-induced necrosis and liver injury. Hepatology :
Chao, Honglu; Anthonymuthu, Tamil S; Kenny, Elizabeth M et al. (2018) Disentangling oxidation/hydrolysis reactions of brain mitochondrial cardiolipins in pathogenesis of traumatic injury. JCI Insight 3:
Steinman, Justin; Epperly, Michael; Hou, Wen et al. (2018) Improved Total-Body Irradiation Survival by Delivery of Two Radiation Mitigators that Target Distinct Cell Death Pathways. Radiat Res 189:68-83

Showing the most recent 10 out of 203 publications