There is a perceived threat of exposure of a sizable human population to radiation through terrorist action. Currently, there is only one chemical, amifostine, approved as a radioprotector, which is rather toxic at its therapeutic dose. There is an urgent need for more such chemicals for the mitigation and treatment of radiation injury. Genetic instability, including DNA deletions are involved in cell death, cellular dysfunction as well as long-term consequences such as birth defects and maybe other degenerative diseases. Radiation causes DNA strand breaks resulting in genetic instability and DNA deletions. We have previously shown that DNA deletions are inducible by ionizing radiation in yeast, human cells as well as in vivo in mice. In the previous budget period we have developed a high tliroughput assay with yeast and used this assay to search for chemicals that reduce cell killing as well as DNA deletions from the ASINEX chemical library. Very interestingly, these chemicals turned out to be potent radiation mitigators in mice, when the first dose was applied 24 hours after irradiation. In addition, they significantly reduced the frequency of radiation-induced cancer.
In aim 1 the HTS DEL assay in yeast will be used to screen for further chemicals from the libraries and from a targeted library around the current radiation mitigators.
In aim 2 we will investigate the effects of the hits from the yeast screen in mammalian cells using a mammalian rearrangement assay.
In aim 3 we are proposing to synthesize targeted chemical libraries around those mitigators and select the most potent mitigator from those libraries. We also propose to screen for new mitigators.
In aim 4 we will also characterize the mitigators using a variety of assays including a functional genomics assay. Using a functional genomics assay we will determine the genetic control of the mitigation effect in order to obtain novel targets for chemical intervention ofthe mitigation ofthe radiation effect. Such novel mechanistic targets can be used to screen for new compounds that specifically interact with such targets potentially yielding an even more potent mitigator.
In aim 5 we will determine radiation mitigation effects ofthe new compounds that we will obtain in vivo.
In aim 6 we propose to characterize the mitigators in animals using information will be obtained from projects 2 and 3 with which project 1 will closely interface.

Public Health Relevance

This will give us further characterization of our novel mitigators of which nothing is currently known and which may have a completely novel mechanism of action. In addition, the further identification of hits from different libraries including targeted libraries around our already identified mitigators is likely to produce even more potent mitigators

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI067769-09
Application #
8513239
Study Section
Special Emphasis Panel (ZAI1-KS-I)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
9
Fiscal Year
2013
Total Cost
$394,603
Indirect Cost
$139,844
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Woods, Kaley; Lee, Percy; Kaprealian, Tania et al. (2018) Cochlea-sparing acoustic neuroma treatment with 4? radiation therapy. Adv Radiat Oncol 3:100-107
Murray, David; Mirzayans, Razmik; McBride, William H (2018) Defenses against Pro-oxidant Forces - Maintenance of Cellular and Genomic Integrity and Longevity. Radiat Res 190:331-349
McBride, William H; Ganapathy, Ekambaram; Lee, Mi-Heon et al. (2017) A perspective on the impact of radiation therapy on the immune rheostat. Br J Radiol 90:20170272
Sasine, Joshua P; Yeo, Kelly T; Chute, John P (2017) Concise Review: Paracrine Functions of Vascular Niche Cells in Regulating Hematopoietic Stem Cell Fate. Stem Cells Transl Med 6:482-489
Graham, Nicholas A; Minasyan, Aspram; Lomova, Anastasia et al. (2017) Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures. Mol Syst Biol 13:914
Kar, Upendra K; Simonian, Margaret; Whitelegge, Julian P (2017) Integral membrane proteins: bottom-up, top-down and structural proteomics. Expert Rev Proteomics 14:715-723
Duhachek-Muggy, Sara; Bhat, Kruttika; Vlashi, Erina et al. (2017) Growth Differentiation Factor 11 does not Mitigate the Lethal Effects of Total-Abdominal Irradiation. Radiat Res 188:469-475
Himburg, Heather A; Doan, Phuong L; Quarmyne, Mamle et al. (2017) Dickkopf-1 promotes hematopoietic regeneration via direct and niche-mediated mechanisms. Nat Med 23:91-99
Micewicz, Ewa D; Kim, Kwanghee; Iwamoto, Keisuke S et al. (2017) 4-(Nitrophenylsulfonyl)piperazines mitigate radiation damage to multiple tissues. PLoS One 12:e0181577
Purbey, Prabhat K; Scumpia, Philip O; Kim, Peter J et al. (2017) Defined Sensing Mechanisms and Signaling Pathways Contribute to the Global Inflammatory Gene Expression Output Elicited by Ionizing Radiation. Immunity 47:421-434.e3

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