Despite the long history of studying the effects of radiation on normal tissues in vitro and in vivo, there is a dearth of agents immediately available for mitigating radiation injury. The UCLA-CMCR has developed an infrastructure that allows discovery and evaluation of such agents. Most of this effort went into an unbiased approach to drug discovery that employs high throughput screening (HTS) of libraries of chemically defined or known bioactive small molecules using yeast, murine, and human systems and multiple endpoints. Importantly, Projects 1 and 2, which will continue, identified lead compounds and classes of compounds from both types of libraries that can mitigate damage in vivo when given to mice 24 hrs after lethal whole body radiation doses. """"""""Core"""""""" chemical structures have been identified, so part of the focus in the next funding period will be on synthesizing analogues to hone in on the critical elements responsible for activity, with a view to optimizing drug effectiveness and delivery through pharmaceutical chemistry. We have validated our original concept that molecular and chemical """"""""signatures"""""""" can be used to classify modulators of radiation responses and that these can then be exploited for rational development of effective mitigating agents. We have knowledge of mechanisms for several classes of compounds, but several others still need to be further investigated. Some act through Toll-like receptors, as described in this application, and Project 3 now focuses on this pathway. Further drug discovery efforts are underway. The UCLA-CMCR has harnessed multiple strengths at UCLA with benefit to the CMCR program and has built a rich environment for research, training, and product development in the radiation sciences. This renewal incorporates investigators, information, and experimental systems from eight pilot projects, in addition to existing personnel. All information is stored on an industrial-strength database so that all CMCRs can have access for analysis and data mining. We interact with other members of the CMCR network and with groups and individuals in academic and commercial entities to test and compare mitigators. In brief, the UCLA-CMCR has made great progress and has developed many promising avenues for future exploration.

Public Health Relevance

There are few agents that can be given to radiation exposed individuals to mitigate harm. This program has developed new mitigators by screening tens of thousands of compounds for effectiveness. The lead compounds that have been identified will now be further tested and examined for efficacy, ease of delivery, and safety so that they can be readily given to the public in a radiological emergency.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-KS-I (M1))
Program Officer
Macchiarini, Francesca
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Schools of Medicine
Los Angeles
United States
Zip Code
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
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
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
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
Micewicz, Ewa D; Kim, Kwanghee; Iwamoto, Keisuke S et al. (2017) 4-(Nitrophenylsulfonyl)piperazines mitigate radiation damage to multiple tissues. PLoS One 12:e0181577
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
Wang, Wenyuan; Org, Tonis; Montel-Hagen, Amélie et al. (2016) MEF2C protects bone marrow B-lymphoid progenitors during stress haematopoiesis. Nat Commun 7:12376
Sun, Yujie; Kaur, Kawaljit; Kanayama, Keiichi et al. (2016) Plasticity of Myeloid Cells during Oral Barrier Wound Healing and the Development of Bisphosphonate-related Osteonecrosis of the Jaw. J Biol Chem 291:20602-16
Himburg, Heather A; Sasine, Joshua; Yan, Xiao et al. (2016) A Molecular Profile of the Endothelial Cell Response to Ionizing Radiation. Radiat Res 186:141-52
Yan, Xiao; Himburg, Heather A; Pohl, Katherine et al. (2016) Deletion of the Imprinted Gene Grb10 Promotes Hematopoietic Stem Cell Self-Renewal and Regeneration. Cell Rep 17:1584-1594

Showing the most recent 10 out of 90 publications