Nrf2 and Radiation-induced pulmonary fibrosis.

描述（由申请人提供）：放射诱导肺纤维化（RiPF）是一种由放射治疗引发的“晚期正常组织肺损伤”，可导致癌症幸存者的显著发病率和死亡率。尽管在确定引起RiPF的病理生理事件方面已经取得了进展，但关于这种辐射诱导的晚期效应的分子基础知识仍存在很大差距。我们的长期目标是确定调节RiPF易感性的因素并阐明其分子机制，以便最终制定预防和/或减轻RiPF的治疗策略。这个应用程序的目的是在因素之间提供一种机制上的联系

DESCRIPTION (provided by applicant): 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.