In light of the current state of heightened terrorism risk, an easily assessed, well-characterized and broadly applicable biodosimeter is urgently required in order to identify those personnel that may be susceptible to the morbidity and mortality associated with the pulmonary consequences of a mass radiological or nuclear event. Indeed, due to our increased ability to care for victims of acute accidental (or intentional) exposure, exposed persons are more likely to survive the immediate hematological crises which result from whole body exposure; however late morbidities then can occur as part of a multi-organ dysfunction syndrome. Therefore, the down- stream roles played by such organs as the lung in this syndrome's progression are of increasing concern and need to be identified in order to employ timely mitigation. We believe that we have identified a potential biomarker of radiation-induced lung late effect progression, Clara cell secretory protein (CCSP/CC16), which is expressed in an injury-specific pattern, identifiable in the plasma. In order to fully characterze this biomarker, we will make use of a pertinent 2-strain murine model, thereby covering the spectrum of lung endpoints seen in the human population. In addition, we will assess the differential expression pattern of the biomarker in two special populations, children and the elderly, through the use of neonate and aged mouse models. The three specific aims include: 1. To test the hypothesis that changes in the amount of Clara cell secretory protein (CCSP or CC16) versus surfactant protein-D (SP-D) expression in the plasma of irradiated animals will predict the incidence and progression of radiation fibrosis; 2. To test the specificity of the CCSP marker in other models of lung injury that result in an inflammatory and/or fibrotic response; 3. To determine the utility of CCSP as a marker of chronic lung injury in a special population. The value of such biomarkers exists both in their ability to predict the progression of disease following exposure and their usefulness in evaluating the efficacy of mitigation strategies that may be employed to prevent such injury. Importantly, the biomarkers being sought in this effort are markers of effect, and not markers of dose, thereby providing the additional information required before making critical decisions regarding potential interventions. We anticipate that by the end of the funding period, we will have identified the time- and dose-specific patterns of expression of CCSP, a biomarker that could potentially then be developed for use in both the immediate and delayed periods following a radiological event.

Public Health Relevance

This grant is aimed at fully characterizing a biomarker of radiation-induced lung late effects, making use of a pertinent '2-strain' murine model that covers the spectrum of lung endpoints seen in the human population. In addition, we will assess the differential expression pattern of the biomarker in two special populations, children and the elderly, through the use of neonate and aged mouse models. We anticipate that by the end of the funding period, we will have identified the time- and dose-specific patterns of expression of Clara cell secretory protein (CCSP), a biomarker that could potentially then be developed for use in both the immediate and delayed periods following a radiological event.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
4R01AI101732-05
Application #
9064075
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Vedamony, Merriline M
Project Start
2012-06-01
Project End
2017-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Rochester
Department
Pediatrics
Type
School of Medicine & Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Beach, Tyler A; Groves, Angela M; Johnston, Carl J et al. (2018) Recurrent DNA damage is associated with persistent injury in progressive radiation-induced pulmonary fibrosis. Int J Radiat Biol 94:1104-1115
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
Groves, Angela M; Johnston, Carl J; Misra, Ravi S et al. (2016) Effects of IL-4 on pulmonary fibrosis and the accumulation and phenotype of macrophage subpopulations following thoracic irradiation. Int J Radiat Biol 92:754-765
Groves, Angela M; Johnston, Carl J; Misra, Ravi S et al. (2015) Whole-Lung Irradiation Results in Pulmonary Macrophage Alterations that are Subpopulation and Strain Specific. Radiat Res 184:639-49
Misra, Ravi S; Johnston, Carl J; Groves, Angela M et al. (2015) Examining the Effects of External or Internal Radiation Exposure of Juvenile Mice on Late Morbidity after Infection with Influenza A. Radiat Res 184:3-13
Rangel-Moreno, Javier; de la Luz Garcia-Hernandez, Maria; Ramos-Payan, Rosalio et al. (2015) Long-Lasting Impact of Neonatal Exposure to Total Body Gamma Radiation on Secondary Lymphoid Organ Structure and Function. Radiat Res 184:352-66