Radiation-induced pulmonary fibrosis (RiPF) is a 'late normal tissue lung injury'initiated by radiation therapy and can result in significant morbidity ad mortality among cancer survivors. Although progress has been made toward identifying pathophysiological events that give rise to RiPF, there is a substantial gap in knowledge regarding the molecular under-pinnings responsible for this radiation-induced late effect. Our long- term goal is to identify factors that regulate RiPF susceptibility and elucidate their molecular mechanisms in order to ultimately devise therapeutic strategies for preventing and/or mitigating RiPF. The objective of this application is to provide a mechanistic link between factors that regulate TGF-?1/Smad3 signaling and RiPF. Our central hypothesis is that the transcription factor Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a critical molecule for regulating TGF ?-mediated RiPF and this is based on our preliminary and published data.
Three aims will be used to test this hypothesis.
Aim 1 will test the working hypothesis that Nrf2 repressesTGF-?1/Smad3 fibrogenic signaling.
This aim will determine if Nrf2-mediated repression of TGF- ?1/Smad signaling is specific for a subset of profibrotic genes or represents a global mechanism of repression. A ChIP-sequencing/bioinformatics analysis will be used to identify Nrf2-promoter interactions at CAGA sites in TGF-?1/Smad3-regulated fibrosis-inducing genes in primary pulmonary fibroblast and alveolar epithelial type II (AET II) cells. In vivo experimentation will b used to validate a mechanistic link between Nrf2 and fibrotic TGF-? signaling.
Aim 2 will determine the origin of myofibroblast recruitment following thoracic irradiation and test whether recruitment is Nrf2 dependent. Fibrotic TGF-? signaling involves complex circuitry. Research outlined in this aim focuses on a key pathway: recruitment of collagen/matrix secreting myofibroblasts, self perpetuating cells critical for development of pulmonary fibrosis. Yet their cell-of-origin in RiPF is not well characterized. We will use Cre-lox technology/cell fate reporter mice and bone marrow chimera experimentation to determine the contribution of resident fibroblasts, AET II cells, and bone marrow- derived fibrocytes to myofibroblast formation and whether recruitment is Nrf2 dependent.
Aim 3 will test the hypothesis that an Nrf2 deficiency increases the occurrence of radiation-induced life-threatening pulmonary injury.
This aim will use genetically engineered Nrf2 mice to address this proof of concept. The goal is to relate a cell-specific Nrf2 deficiency with phenotype. Successful completion of Aim 1 will identify a new paradigm for Nrf2 signaling.
Aim 2 will connect Nrf2 signaling with pathophysiological recruitment of myofibroblasts.
Aim 3 addresses outcome.
These aims have the potential to provide novel mechanistic insights into RiPF, leading eventually to new therapeutic strategies for preventing or mitigating RiPF.

Public Health Relevance

Radiation-induced pulmonary fibrosis (RiPF) is a 'late normal tissue lung injury'initiated by radiation therapy and can produce significant morbidity and mortality among cancer survivors. The research outlined in this application will test the hypothesis that Nrf2, a transcription factor that is suppressed in subsets of human patients, represents a genetic factor that represses onset of RiPF. We will make use of mouse models in which Nrf2 is genetically disrupted or conditionally deleted to achieve our overarching goal: providing a mechanistic link between Nrf2 expression and RiPF in order eventually to develop therapeutic options for cancer survivors.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Radiation Therapeutics and Biology Study Section (RTB)
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Eu, Jerry Pc
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Vanderbilt University Medical Center
Schools of Medicine
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Cameron, Brent D; Sekhar, Konjeti R; Ofori, Maxwell et al. (2018) The Role of Nrf2 in the Response to Normal Tissue Radiation Injury. Radiat Res 190:99-106
Traver, Geri; Mont, Stacey; Gius, David et al. (2017) Loss of Nrf2 promotes alveolar type 2 cell loss in irradiated, fibrotic lung. Free Radic Biol Med 112:578-586
Citrin, Deborah E; Prasanna, Pataje G S; Walker, Amanda J et al. (2017) Radiation-Induced Fibrosis: Mechanisms and Opportunities to Mitigate. Report of an NCI Workshop, September 19, 2016. Radiat Res 188:1-20
Mont, Stacey; Davies, Sean S; Roberts Second, L Jackson et al. (2016) Accumulation of isolevuglandin-modified protein in normal and fibrotic lung. Sci Rep 6:24919
Sekhar, Konjeti R; Freeman, Michael L (2015) Nrf2 promotes survival following exposure to ionizing radiation. Free Radic Biol Med 88:268-274