NRF Transcription Factors in Environmental Stress and Disease Intervention

NRF转录因子在环境应激和疾病干预中的作用 项目摘要 我广泛的研究计划包括深入的机制调查砷发病机理/NRF 信号传导和基本机制知识的转化为临床前药物开发。慢性 砷是一种环境污染物，影响着全世界约1.6亿人， 全球公共卫生问题与发展某些类型癌症的风险增加有关，以及 II型糖尿病然而，在我们关于精确的病理学方面的知识中仍然存在着一个关键的空白。 砷的机制，以及可行的治疗方法的产生。在过去的十年里，我的研究 揭示了NRF 2信号通路的失调是砷基病理学的关键驱动因素。 因此，我的总体愿景是利用我们身体的防御系统-特别是NRF 2 反应-减轻砷引起的损伤或发病。转录因子NRF 2控制着 暴露于环境损伤后的细胞应激反应。自从发现NRF 2通路以来， 在1999年，NRF 2被认为是一种“好的”转录因子，可以防止与氧化应激相关的疾病。 疾病，包括癌症，以及使用NRF 2诱导化合物来预防NRF 2的受控活化， 癌症的发生是公认的。然而，在2008年，我的实验室揭开了NRF 2的“黑暗面”--不受控制的 NRF 2活化是癌症进展、转移和对治疗的抗性的驱动因素。此外，最近 我实验室未发表的工作表明，NRF 2的长期上调也可能有助于 砷的致糖尿病作用因此，特异性NRF 2抑制剂将是用于解剖肿瘤的有力探针。 NRF 2在疾病中的“黑暗面”作用。该领域的一大挑战是没有NRF 2特异性抑制剂 尽管做出了努力。 因此，需要解决的关键科学问题，也是R35的重点 建议，包括：（一）与砷暴露有关的疾病的分子基础（重点是肺 癌症和II型糖尿病）;（ii）环境应激对NRF 2信号网络的影响;（iii） 我们可以利用NRF 2反应改善人类健康的方法;以及（iv） cap 'n'collar（CNC）家族成员NRF 1、NRF 2和NRF 3。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目前的空白， 环境健康研究，最终改善人类健康。

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 Furthermore, recent unpublished work from my lab has indicated that prolonged upregulation of NRF2 may also contribute to the diabetogenic effects of arsenic.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.