The increasing global energy demands and ensuing threat, be it accidental or intentional, of the release of nuclear material require a greater understanding of how to treat and mitigate radiation injury. While many studies describe the nature ofthe host response to radiation injury, established models provide very compelling evidence for a role for innate immunity in the process. Pathogen associated molecular patterns (PAMPs) released following gut injury stimulate tissue repair and host immune pathways. A recently described class of endogenous ligands released by injured cells, the damage associated molecular patterns (DAMPs), stimulate a similar group of innate immune receptors and so instigate a related program of tissue repair. These observations emphasize the point that very similar gene programs are involved in radiation repair and host immunity. The UCLA-CMCR has identified a number of different compounds and small molecules that are successful mitigators of radiation damage;the majority of which activate similar pathways as pathogens. From this comes the emerging understanding that a successful radiation mitigator suppresses excessive inflammation and supports robust regenerative gene programs leading to tissue repair. The optimal balance is exampled by lead compounds such as MIS416, an immune adjuvant that can successfully mediate crosstalk between Innate stimulation and radiation repair by regulating a number of signaling pathways. The same is true for other lead mitigators, such as IL-12, anti-inflammatory small molecules, or Tilorone, a type I interferon inducer. However, the molecular mechanisms responsible for mitigation remain unclear. In this application, we propose to discover which ofthe innate system pattern recognition receptors and which signal transduction pathways are required to support the mitigating activity of MIS416 and other UCLA-CMCR lead molecules. Furthermore, we will determine which genetic programs or cytokines contribute to the mitigating mechanism by inducing regeneration of hematopoietic stem cells. Thirdly, utilizing this increased understanding of the interaction between lead mitigators and innate immune regulatory systems, we shall develop a nanovesicle platform for radiation mitigation. Finally, we will examine a live vaccine model to explore the crosstalk between tissue repair mechanisms utilized in response to radiation injury and infection. Our proposed studies, by dissecting the receptors and pathways that mitigate radiation injury, will provide novel targets for therapeutic intervention and lead molecule verification. Our improved understanding ofthe similarities between responses activated by radiation and infection will drive design of additional novel strategies for intervention.

Public Health Relevance

In the event of a nuclear disaster or accident, strategies that can be used to treat exposed individuals will greatly diminish the impact of radiation injury. We recognize that therapeutics that may help can be derived from agents that cause infection, as recovery from an infection requires many ofthe same immunologic tools as recovery from radiation exposure. This proposal seeks to understand how drugs and strategies described at UCI_A alter the impact of radiation injury and to define targets for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI067769-07
Application #
8307852
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
7
Fiscal Year
2011
Total Cost
$473,378
Indirect Cost
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
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
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

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