NRF2-ARE PATHWAYS: DISCOVERY OF NOVEL CHEMOPREVENTIVE COMPOUNDS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 化学预防是一种创新的策略，其重点是开发药理学、生物学或营养干预措施，在不同阶段阻止、阻止或逆转癌症的发生，以预防和治疗癌症。已经探索了合成或饮食化合物来进行化学预防。然而，可用于化学预防研究的有效和安全的化合物非常有限。这项提议的目标是发现新的和有效的化合物，这些化合物有可能进一步开发为化学预防药物或生物医学研究工具。 I相细胞色素P450(CYP)酶对外源或内源生物具有生物活性，常常产生高活性的亲电体，导致DNA和蛋白质的损伤。第二阶段的酶使第一阶段的代谢产物解毒。I期和II期酶水平之间的生理平衡决定了个体在癌症发生过程中暴露于致癌物质的敏感性或风险。因此，提高II相解毒酶活性将是一种有效的化学预防策略。 核因子-红系P45相关因子2(Nrf2)是一种高效的转录因子。它与抗氧化剂反应元件(ARE)结合，ARE存在于编码许多II相解毒酶和抗氧化蛋白的基因中，在这些基因的协调和诱导表达中起着至关重要的作用。NRF2已被认为是一种新的化学预防的分子靶点。我们假设，使用一个识别良好的Nrf2-ARE途径和基于细胞的高通量筛选策略，可以发现和鉴定特异诱导II相解毒酶和抗氧化蛋白的有效化合物。为了追求我们的目标，我们定义了两个具体的目标。具体目标1：寻找能够特异性激活Nrf2-ARE途径的新化合物。特定目标2：评价从特定目标1中鉴定的特定Nrf2激活剂的生物学效应。 新的、有效的和特异的NRF2激活剂的发现和鉴定将推动化学预防研究的发展，为进一步开发化学预防药物和研究工具提供新的候选药物。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Chemoprevention is an innovative strategy focusing on the development of pharmacalogical, biological, or nutritional interventions to impede, arrest, or reverse carcinogenesis at various stages in order to prevent and treat cancer. Synthetic or dietary compounds have been explored for chemoprevention. However, potent and safe compounds availalbe in chemopreventive research are very limited. The goal of this proposal is to discover novel and potent compounds, which potentially can be further developed as chemopreventive drugs or biomedical research tools. Phase I cytochrome P450 (CYP) enzymes bioactivate xenobiotics or endobiotics, which often produce highly reactive electrophiles leading to damage of DNA and proteins. Phase II enzymes detoxify the phase I metabolic products. Physiological balance between phase I and II enzyme levels determines the sensitivitiy or risk of an individual exposed to carcinogenic species in cancer development. Therefore, enhancement of phase II detoxifying enzyme activities would be an effective strategy for chemoprevention. Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) is a potent transcription factor. It binds to an antioxidant response element (ARE), which exists in genes encoding many phase II detoxifying enzymes and antioxidant proteins, and plays a vital role in consituitive and inducible expression of these genes. Nrf2 has been recognized as a novel molecular target for chemoprevention. We hypothesize that using a well-identified Nrf2-ARE pathway and a cell-based high throughput screening strategy, potent compounds, which specifically induce phase II detoxifying enzymes and antioxidant proteins, can be discovered and identified. Two specific aims are defined to purse our goal. Specific Aim 1: Identify novel compounds which specifically activate Nrf2-ARE pathway. Specific Aim 2: Evaluate the biological effects of specific Nrf2 activators identified from Specific Aim 1. Discovery and identification of novel, potent, and specific Nrf2 activators will move forward the chemopreventive research by providing new candidates for further development as chemopreventive agents and research tools.