NRF Transcription Factors in Environmental Stress and Disease Intervention

NRF 转录因子在环境压力和疾病干预中的作用

• 批准号: 10171851
• 负责人: Donna D Zhang
• 金额: $ 91.82万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10171851
• 关键词: Address; Affect; Arsenic; Cellular Stress Response; Chronic; Disease; Environmental Health; Environmental Pollution; Exposure to; Family member; Generations; Goals; Health; Human; Intervention; Investigation; Knowledge; Malignant Neoplasms; Malignant neoplasm of lung; Molecular; Neoplasm Metastasis; Non-Insulin-Dependent Diabetes Mellitus; Oxidative Stress; Pathogenesis; Pathologic; Pathology; Pathway interactions; Preclinical Drug Development; Public Health; Research; Risk; Role; Side; Signal Pathway; Signal Transduction; Stress; System; Therapeutic; Translations; Up-Regulation; Vision; base; cancer initiation; cancer type; diabetogenic; improved; inhibitor/antagonist; innovation; prevent; programs; response; therapy resistant; transcription factor; tumor progression; unpublished works

Title: NRF transcription factors in Environmental Stress and Disease Intervention PROJECT SUMMARY My broad research program includes in-depth mechanistic investigations of arsenic pathogenesis/NRF signaling and the translation of basic mechanistic knowledge to preclinical drug development. Chronic exposure to arsenic, an environmental contaminant that affects an estimated 160 million people worldwide, is a global public health concern correlated with an increased risk of developing certain types of cancer, as well as type II diabetes. However, a critical gap still exists in our knowledge concerning the precise pathologic mechanisms of arsenic, and generation of viable therapeutic approaches. Over the past decade, my research has revealed that dysregulation of the NRF2 signaling pathway is a key driver of arsenic-based pathologies. Accordingly, my overarching vision is to harness our body's defense systems—specifically the NRF2 response—to alleviate the damage or pathogenesis induced by arsenic. Transcription factor NRF2 controls the cellular stress response following exposure to environmental insults. Since the discovery of the NRF2 pathway in 1999, NRF2 has been viewed as a “good” transcription factor that protects against oxidative stress-related diseases, including cancer, and controlled activation of NRF2 using NRF2-inducing compounds to prevent cancer initiation is well recognized. However, in 2008 my lab unveiled the “dark side” of NRF2—uncontrolled NRF2 activation is a driver of cancer progression, metastasis, and resistance to therapy. Furthermore, recent unpublished work from my lab has indicated that prolonged upregulation of NRF2 may also contribute to the diabetogenic effects of arsenic. Therefore, specific NRF2 inhibitors will be powerful probes for dissecting the “dark side” role of NRF2 in disease. A big challenge in the field is that there are no NRF2-specific inhibitors available despite the efforts made. Therefore, the key scientific questions that need to be addressed, and as such are the focus of this R35 proposal, include: (i) the molecular basis of diseases associated with arsenic exposure (focusing on lung cancer and type II diabetes); (ii) the effects of environmental stress on the NRF2 signaling network; (iii) the ways by which we can harness the NRF2 response to improve human health; and (iv) the distinct roles of the cap'n'collar (CNC) family members NRF1, NRF2, and NRF3. My lab will pursue answers to these questions through innovative and rigorous experimental approaches, which will allow us to fill current gaps, advance environmental health research, and ultimately improve human health.

标题：NRF 转录因子在环境压力和疾病干预中的作用 项目概要 我的广泛研究计划包括砷发病机制/NRF 的深入机制研究 信号传导和基本机械知识到临床前药物开发的转化。慢性的 砷是一种环境污染物，估计影响全世界 1.6 亿人， 全球公共卫生问题与罹患某些类型癌症的风险增加相关，以及 II型糖尿病。然而，我们对精确病理学的了解仍然存在重大差距。 砷的机制，以及可行的治疗方法的产生。过去十年来，我的研究 研究表明，NRF2 信号通路的失调是砷相关疾病的关键驱动因素。 因此，我的首要愿景是利用我们身体的防御系统，特别是 NRF2 反应——减轻砷引起的损害或发病机制。转录因子 NRF2 控制 暴露于环境损害后的细胞应激反应。自从NRF2通路被发现以来 1999年，NRF2被认为是一种“好的”转录因子，可以防止氧化应激相关的 疾病，包括癌症，以及使用 NRF2 诱导化合物控制 NRF2 激活以预防 癌症的发生是众所周知的。然而，2008 年，我的实验室揭开了 NRF2 的“阴暗面”——不受控制 NRF2 激活是癌症进展、转移和治疗耐药的驱动因素。此外，最近 我的实验室未发表的工作表明，NRF2 的长期上调也可能有助于 砷的致糖尿病作用。因此，特异性 NRF2 抑制剂将成为剖析 NRF2 的有力探针。 NRF2 在疾病中的“阴暗面”作用。该领域的一大挑战是没有 NRF2 特异性抑制剂 尽管做出了努力，仍然可以使用。 因此，需要解决的关键科学问题也是本 R35 的重点 提案包括：(i) 与砷暴露相关的疾病的分子基础（重点是肺 癌症和 II 型糖尿病）； (ii) 环境压力对NRF2信号网络的影响； (三) 我们如何利用 NRF2 反应来改善人类健康； (iv) 的独特角色 cap'n'collar (CNC) 家族成员 NRF1、NRF2 和 NRF3。我的实验室将寻求这些问题的答案 通过创新和严格的实验方法，这将使我们能够填补当前的空白，推进 环境健康研究，最终改善人类健康。