NRF Transcription Factors in Environmental Stress and Disease Intervention

环境应激与疾病干预中的NRF转录因子 项目总结 我的广泛研究计划包括深入研究砷的发病机制/NRF 信号传递和基础机制知识向临床前药物开发的转化。慢性 接触砷是一种环境污染物，估计影响全球1.6亿人，是一种 全球公共卫生关切与患某些类型癌症的风险增加有关，以及 II型糖尿病。然而，在精确的病理学方面，我们的知识中仍然存在着一个关键的缺口。 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 研究表明，NRF2信号通路的失调是砷致病的关键驱动因素。 因此，我的总体愿景是利用我们身体的防御系统--特别是NRF2 反应-减轻砷引起的损害或致病。转录因子NRF2控制 暴露于环境侮辱后的细胞应激反应。自从发现NRF2通路以来 1999年，nrf2被认为是一种“良好的”转录因子，可以保护人类免受氧化应激的伤害。 疾病，包括癌症，以及使用NRF2诱导化合物控制激活NRF2以防止 癌症的发生是公认的。然而，在2008年，我的实验室揭露了NRF2的“阴暗面”--不受控制 NRF2的激活是癌症进展、转移和抵抗治疗的驱动因素。此外，最近 我的实验室未发表的研究表明，NRF2的长期上调也可能有助于 砷的致糖尿病作用。因此，特异性的NRF2抑制剂将成为解剖肿瘤的有力探针。 NRF2在疾病中的“黑暗面”作用。该领域的一大挑战是没有NRF2特异性的抑制剂 尽管作出了努力，但仍可获得。 因此，需要解决的关键科学问题，因此是R35的重点 提议，包括：(1)与砷暴露有关的疾病的分子基础(重点是肺部 癌症和II型糖尿病)；(Ii)环境应激对NRF2信号网络的影响； 我们可以利用NRF2反应来改善人类健康的方法；以及(Iv) 帽领(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目前的空白，取得进展 环境健康研究，并最终改善人类健康。

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 Furthermore, recent unpublished work from my lab has indicated that prolonged upregulation of NRF2 may also contribute to the diabetogenic effects of arsenic.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