The focus of the University of Rochester CMCR is drug development, in particular investigating agents targeted at specific, late endpoints in four primary and critical organs and tissues: the lung (Project 1), brain (Project 2), skin (Project 3) and bone marrow (Project 4). Indeed, inherent to the composition of the proposed Center is the high degree of synergism between the projects which is critical to the Center's goal of developing mitigating agents in the context of a systemic injury, since it will allow for the interchange of tissues between projects for analysis and correlation of data. To this end, each of the projects will use the same animal strain, the same radiation delivery protocols, and the same drug dose protocols, when appropriate. Each project incorporates models of external irradiation (TBI) and contamination, combined injury (concurrent or sequential), and will assess differential responses in adult and neonate animals, the latter acting as a surrogate for the pediatric population. Moreover, we also have available a CMCR """"""""Unique Facility,"""""""" our internal contamination chamber developed during the previous funding period. In addition to analyses being carried out by individual projects, standardized image analysis and histological preparation will be performed through Core C, Imaging &Histopathology. Thus, a secondary objective for each of the projects will be the assessment of agents being developed by the other projects in terms of effectiveness and possible toxicological sequelae in their own tissue of interest. Much of this secondary analysis will be performed through the statistical component of Core D, Drug Translation and Development. Our Drug Core will oversee the development of the following agents: Homspera(r): an analogue of Substance P which is involved in the pathophysiology of numerous inflammatory diseases. Two of the Projects, 1 (lung) and 4 (bone marrow), will assess Homspera on their late endpoints, pulmonary fibrosis and late hematopoiesis dysfunction, respectively. Minocycline: a well-tolerated and safe antibiotic and anti-inflammatory that readily crosses the blood-brain barrier. Project 2 will assess the effect of minocycline on its endpoint, radiation-induced neuroinflammation. IL-12: Not only does IL-12 trigger DNA repair through nucleotide excision repair, but it also may play a role in initiating repair of the principal injury induced by ionizing radiation, i.e. double strand breaks. Project 3 will further assess the effectiveness of IL-12 in its radiation and combined injury models. Eukarion Series: EUK-189 and EUK-207 have mitigation activity in various in vivo models for radiation-induced injury. Projects 1, 2, and 4 will assess the effectiveness of EUK-207 on their respective endpoints;Project 3 will assess the effectiveness of a topical formulation of EUK-189. Tetrahydrocurcumin: Project 3 will make use of both the anti-inflammatory and radical scavenging properties of tetrahydrocurcumin;this agent will be administered topically. SecinH3 has been shown to stabilize the endothelium and inhibit pathologic angiogenesis and vascular leak induced by cytokines and growth factors. SecinH3 will be tested in Projects 1 and 2.

Public Health Relevance

The multiplicity and criticality of the organs being assessed in our Center has relevance to the radiological terrorism scenario since it is likely that the dose distribution will be highly heterogeneous and will result, in many cases, in one organ or tissue appearing to be more adversely affected than others. However, the specific questions and endpoints being addressed by each of the projects within the proposal derive from our central hypothesis that the individual late effects will develop in the context of a systemic injury and will form part of a radiation-induced, multiple organ dysfunction or failure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI091036-05
Application #
8705362
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Macchiarini, Francesca
Project Start
2010-08-01
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Rochester
Department
Radiation-Diagnostic/Oncology
Type
School of Medicine & Dentistry
DUNS #
City
Rochester
State
NY
Country
United States
Zip Code
14627
Begolly, Sage; Olschowka, John A; Love, Tanzy et al. (2018) Fractionation enhances acute oligodendrocyte progenitor cell radiation sensitivity and leads to long term depletion. Glia 66:846-861
Dunlap, Micah D; Howard, Nicole; Das, Shibali et al. (2018) A novel role for C-C motif chemokine receptor 2 during infection with hypervirulent Mycobacterium tuberculosis. Mucosal Immunol 11:1727-1742
Howard, Nicole C; Marin, Nancy D; Ahmed, Mushtaq et al. (2018) Mycobacterium tuberculosis carrying a rifampicin drug resistance mutation reprograms macrophage metabolism through cell wall lipid changes. Nat Microbiol 3:1099-1108
Groves, Angela M; Johnston, Carl J; Williams, Jacqueline P et al. (2018) Role of Infiltrating Monocytes in the Development of Radiation-Induced Pulmonary Fibrosis. Radiat Res 189:300-311
Beach, Tyler A; Johnston, Carl J; Groves, Angela M et al. (2017) Radiation induced pulmonary fibrosis as a model of progressive fibrosis: Contributions of DNA damage, inflammatory response and cellular senescence genes. Exp Lung Res 43:134-149
Domingo-Gonzalez, Racquel; Das, Shibali; Griffiths, Kristin L et al. (2017) Interleukin-17 limits hypoxia-inducible factor 1? and development of hypoxic granulomas during tuberculosis. JCI Insight 2:
Judge, Jennifer L; Lacy, Shannon H; Ku, Wei-Yao et al. (2017) The Lactate Dehydrogenase Inhibitor Gossypol Inhibits Radiation-Induced Pulmonary Fibrosis. Radiat Res 188:35-43
Sweet, Tara B; Hurley, Sean D; Wu, Michael D et al. (2016) Neurogenic Effects of Low-Dose Whole-Body HZE (Fe) Ion and Gamma Irradiation. Radiat Res 186:614-623
Moravan, Michael J; Olschowka, John A; Williams, Jacqueline P et al. (2016) Brain radiation injury leads to a dose- and time-dependent recruitment of peripheral myeloid cells that depends on CCR2 signaling. J Neuroinflammation 13:30
Begolly, Sage; Shrager, Peter G; Olschowka, John A et al. (2016) Fractionation Spares Mice From Radiation-Induced Reductions in Weight Gain But Does Not Prevent Late Oligodendrocyte Lineage Side Effects. Int J Radiat Oncol Biol Phys 96:449-457

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