NRF2-ARE PATHWAYS: DISCOVERY OF NOVEL CHEMOPREVENTIVE COMPOUNDS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 化学预防是一种创新策略，专注于开发药理学，生物学或营养干预措施，以阻止，阻止或逆转各个阶段的致癌作用，以预防和治疗癌症。 已经探索了合成或膳食化合物用于化学预防。 然而，有效和安全的化合物可用于化学预防研究是非常有限的。 该提案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）酶生物活化异生物质或内生生物质，其通常产生导致DNA和蛋白质损伤的高度反应性亲电体。 II相酶解毒I相代谢产物。 I相和II相酶水平之间的生理平衡决定了个体在癌症发展中暴露于致癌物质的敏感性或风险。 因此，增强II相解毒酶活性将是一种有效的化学预防策略。 核因子-红细胞2 p45相关因子2（Nrf 2）是一种有效的转录因子。 它与抗氧化反应元件（ARE）结合，该元件存在于编码许多II相解毒酶和抗氧化蛋白的基因中，并在这些基因的组成性和诱导性表达中起重要作用。 nrf 2已被公认为是一种新的化学预防的分子靶点。 我们假设，使用一个明确的Nrf 2-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性诱导II期解毒酶和抗氧化蛋白的有效化合物。 为了实现这一目标，本文确定了两个具体目标。 具体目标1：鉴定特异性激活Nrf 2-ARE途径的新型化合物。 具体目标2：评价从具体目标1中识别的特定Nrf 2激活剂的生物学效应。 发现和鉴定新的、有效的和特异性的Nrf 2激活剂将通过提供新的候选物作为化学预防剂和研究工具来进一步发展化学预防研究。

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.