Elimination of dietary aflatoxin to prevent liver cancer

描述（由申请人提供）：我们的长期目标是通过消除饮食中的黄曲霉毒素和人类暴露于食物中的这种霉菌毒素来预防肝癌。在过去的研究中，我们在实现这一长期目标方面取得了重大进展，并实现了两个短期目标。(1)我们确定了激活黄曲霉毒素基因表达的遗传开关中的关键成分，并开发了一个全面的模型，预测开关调节黄曲霉毒素合成的时间和水平的详细机制。(2)我们确定了几种真菌和植物的代谢产物，阻止黄曲霉毒素的积累和基因表达。在本研究的下一阶段，我们将充分详细地分析开关机制的两个关键组成部分，以确定易受控制的具体步骤。利用这些信息，我们将继续鉴定和测试有前途的天然植物和真菌化合物，阻止黄曲霉毒素的合成。这种研究方法将使我们能够确认或修改调控模型中的关键步骤，并将填补我们对黄曲霉毒素合成的理解和对复杂基因簇的控制的关键知识空白。这一方法还将有助于制定和应用有效的策略，阻止易感作物合成黄曲霉毒素。基于我们的遗传开关模型，我们提出了两个中心假设：1）活性CRE 1bp复合物募集启动黄曲霉毒素基因表达所需的蛋白质（AflR和HAT）; 2）黄曲霉毒素基因激活的时间和水平部分地由黄曲霉毒素基因簇中组蛋白H4乙酰化的启动和扩散控制。为了解决这些假设，我们建议实现两个具体目标。1.分析CRE 1bp在黄曲霉毒素基因激活中的作用。2.分析组蛋白H4乙酰化在黄曲霉毒素基因激活中的作用。作为每个特定目标的拟议工作的一部分，我们将确定新的黄曲霉毒素合成抑制剂，并确定这些和以前确定的抑制剂阻断黄曲霉毒素合成的具体机制。我们的工作将使我们能够有效地控制食品和饲料作物上的黄曲霉毒素合成-这一结果将通过提供一种降低肝癌发病率的实用策略对人类健康产生巨大的积极影响。公共卫生相关性：作为拟议工作的一部分，我们将确定新的黄曲霉毒素合成抑制剂，并确定这些和以前确定的抑制剂阻断黄曲霉毒素合成的具体机制。我们的工作将使我们能够有效地控制食品和饲料作物上黄曲霉毒素的合成。这一结果将通过提供一种降低肝癌发病率的实用策略对人类健康产生巨大的积极影响。

DESCRIPTION (provided by applicant): Our long-term goal is to prevent liver cancer by eliminating dietary aflatoxin and human exposure to this mycotoxin in food. In past research, we made significant progress towards this long-term goal and accomplished two short-term goals. (1) We identified key components in the genetic switch that activate aflatoxin gene expression and developed a comprehensive model that predicts the detailed mechanisms by which the switch regulates the timing and level of aflatoxin synthesis. (2) We identified several fungal and plant metabolites that block aflatoxin accumulation and gene expression. In the next phase of this research, we will analyze two key components of the switch mechanism in sufficient detail to identify specific steps that are susceptible to control. Using this information, we will continue to identify and test promising natural plant and fungal compounds that block aflatoxin synthesis. This research approach will allow us to confirm or modify key steps in the regulatory model and will fill a critical knowledge gap in our understanding of aflatoxin synthesis specifically and in control of complex gene clusters in general. This approach will also assist efforts to formulate and apply effective strategies to block aflatoxin synthesis on susceptible crops. Based on our model of the genetic switch, we present two central hypotheses: 1) active CRE1bp complexes recruit proteins necessary for initiation of aflatoxin gene expression (AflR and HAT); 2) the timing and level of aflatoxin gene activation is in part controlled by the initiation and spread of histone H4 acetylation in the aflatoxin gene cluster. To address these hypotheses, we propose to accomplish two Specific Aims. 1. Analyze the role of CRE1bp in aflatoxin gene activation. 2. Analyze the role of histone H4 acetylation in aflatoxin gene activation. As part of the proposed work for each specific aim, we will identify new inhibitors of aflatoxin synthesis and determine the specific mechanisms by which these and previously identified inhibitors block aflatoxin synthesis. Our work will allow us to effectively control aflatoxin synthesis on food and feed crops - this outcome will have a large positive impact on human health by providing one practical strategy to reduce liver cancer incidence. PUBLIC HEALTH RELEVANCE: As part of the proposed work, we will identify new inhibitors of aflatoxin synthesis and determine the specific mechanisms by which these and previously identified inhibitors block aflatoxin synthesis. Our work will allow us to effectively control aflatoxin synthesis on food and feed crops. This outcome will have a large positive impact on human health by providing one practical strategy to reduce liver cancer incidence.