PROJECT 1: Acute and Long Term Immune Responses to Radiation and Mitigation PROJECT SUMMARY The long-term goal of this application is to understand the role of immune responses in and the mechanisms responsible for the short and long term diseases caused by exposure to sources of ionizing radiation. One important aspect of radiation injury is the release of both endogenous damage associated molecular patterns (DAMPs) from the damaged tissues and pathogen associated molecular patterns (PAMPs) from the gastrointestinal system. These DAMPs and PAMPs released after irradiation interact with common pattern recognition receptors such as Toll-Like Receptors (TLR) and activate overlapping gene programs to regulate innate and adaptive immune responses as well as tissue damage and repair. In our previous studies, we found that MIS416 ? a particle based on the cell wall components of P. acnes decorated with a single stranded TLR9 ligand CpG-A (Vironyx Corp.) ? which likely contains multiple PAMPs, can function as a mitigator to rescue lethally irradiated mice. We have further evidence that different TLR agonists induce different profiles of growth factors, cytokines and chemokines, suggesting that multiple innate immune pathways might be required to mitigate radiation damage. Based on our results from multiple tissue damage models, we have recently hypothesized that over reactive innate immune responses to DAMPs and PAMPs released after irradiation can further trigger secondary tissue damages by proinflammatory cytokines and autoantibodies. We have further developed a widely available and easily deliverable DAMP blocking compound, glycyrrhizic acid (GA), as a potent radiation mitigator. In addition, while GCSF has been used as a standard mitigator, we have developed a bivalent GCSF (Bi-GCSF) as a more potent and stable radiation mitigator. Through close collaboration with Dr. William McBride's group, we have found that although many mitigators can effectively rescue lethally irradiated mice during acute radiation syndrome (ARS), many rescued mice often develop delayed effects of acute radiation exposure (DEARE) exhibiting chronic diseases such as heart and kidney failures around a year after WBI. Our preliminary studies indicate that these chronic diseases are associated with proinflammatory responses. Based on these studies, we hypothesize that balanced immune and inflammatory responses are critical not only for rescuing acute phase tissue damages but also for preventing chronic diseases caused by radiation. In this application, we will evaluate the effects of individual mitigators on the short and long term innate and adaptive immune systems and further develop a combination of mitigators that can effectively treat both acute and chronic diseases after radiation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI067769-13
Application #
9320907
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
13
Fiscal Year
2017
Total Cost
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
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
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

Showing the most recent 10 out of 93 publications