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innovation; prevent; programs; response; therapy resistant; transcription factor; tumor progression; unpublished works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：环境压力和疾病干预中的NRF转录因子 项目摘要 我的广泛研究计划包括对砷发病机理/NRF的深入机理研究 信号传导和将基本机械知识转化为临床前药物开发。慢性的 暴露于砷是一种影响全球估计1.6亿人的环境污染物，是 全球公共卫生问题与患有某些类型癌症的风险增加有关，以及 II型糖尿病。但是，关于精确病理学的知识，我们的知识仍然存在关键差距 砷的机制和生成可行的治疗方法。在过去的十年中，我的研究 已经揭示了NRF2信号通路的失调是基于砷病理的关键驱动因素。 彼此之间，我的总体愿景是利用我们人体的防御系统，特别是NRF2 反应 - 减轻砷引起的损害或发病机理。转录因子NRF2控制 暴露于环境伤害后的细胞应力反应。自从发现NRF2途径以来 在1999年，NRF2被视为“良好”转录因子，可预防与氧化应激有关的转录因子 使用NRF2诱导的化合物，包括癌症，包括癌症和NRF2的受控激活 癌症倡议众所周知。但是，在2008年，我的实验室揭示了NRF2的“黑暗面” - 没有控制 NRF2激活是癌症进展，转移和对治疗抗性的驱动力。此外，最近 我实验室未发表的工作表明，延长NRF2的上调也可能有助于 砷的糖尿病作用。因此，特定的NRF2抑制剂将是剖析的有力问题 NRF2在疾病中的“黑暗面”作用。该领域的一个巨大挑战是没有NRF2特异性抑制剂 可用于努力。 因此，需要解决的关键科学问题，因此是R35的重点 建议，包括：（i）与砷暴露相关的疾病的分子基础（专注于肺 癌症和II型糖尿病）； （ii）环境应力对NRF2信号网络的影响； （iii） 我们可以利用NRF2响应以改善人类健康的方式； （iv） Cap'n'Collar（CNC）家庭成员NRF1，NRF2和NRF3。我的实验室会回答这些问题 通过创新和严格的实验方法，这将使我们能够填补当前空白，并提高 环境健康研究，并最终改善人类健康。