The long-term goal of this research project is to identify mechanisms by which normal tissue stem cells that initially survive exposure to radiation are expanded in vivo to maintain tissue integrity. The goal of this proposal is to uncover the mechanism of mitigation observed with drugs containing sulfonylpiperazine active groups. We will investigate whether the reconstitution of the normal tissue stem cell pool seen after application of these mitigators is a direct effect on the stem cell populations in the gut and central nervous system (CNS), or mediated by providing a microenvironment permissive for stem cell expansion. Using in vitro and in vivo model systems for acute and late radiation damage we will investigate direct and indirect effects of these drugs on stem cell expansion and plasticity and uncover the underlying signaling events that lead to radiation mitigation. Specifically, we hypothesize that radiation mitigators with sulfonylpiperazine active groups, identified in the previous funding period, affect normal tissue stem cell populations in the gut and CNS directly or indirectly through G-protein-coupled receptor-mediated signaling. The systematic study of the cellular effects of compound #15 in mitigating ARS and DEARE, and uncovering the underlying mechanisms will lay ground for finding and understanding novel dual function mitigators for acute radiation syndrome (ARS) and delayed effects of acute radiation exposure (DEARE). This will have a wide impact on the field, as it will uncover common targets on normal tissue stem cells that can be used to mitigate radiation damage on multiple organ systems simultaneously.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
2U19AI067769-11
Application #
8941363
Study Section
Special Emphasis Panel (ZAI1-PA-I (M2))
Project Start
Project End
Budget Start
2015-08-11
Budget End
2016-07-31
Support Year
11
Fiscal Year
2015
Total Cost
$461,721
Indirect Cost
$151,583
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

Showing the most recent 10 out of 93 publications