The role of environmental organohalogenated contaminants on lipid metabolism and biological action

我们不断地暴露在环境污染物中，因为它们存在于我们的饮食和环境中。众所周知，这些污染物可以操纵由基因和蛋白质调控的基本生物途径。然而，由于污染物与脂质信号分子相互作用的不确定性，对污染物的命运缺乏完全的了解。长期以来，信号脂质一直被认为对生物体的生物过程至关重要。我提出的研究旨在阐明一类新出现的污染物、含氟物质和信号脂质之间的关系，以充分了解基本和高级细胞功能如何对这种暴露做出反应和适应。所获得的结果将使我们能够更好地预测环境污染物暴露后的生物后果。*我和其他人的研究表明，含氟物质可以诱导酶、修饰蛋白质并与受体结合。我假设这些过程与信号脂质活动有关。使用常规用于研究蛋白质信号和基因调控模式的细胞和动物模型，我们可以测量信号脂质，并将其与这些传统研究的途径联系起来。我们将使用遗传学(基因验证)、生化(表征蛋白质)和化学(激活特定靶点的物质)的方法来描述在许多过程中污染物暴露后血脂是如何受到影响的。我们将确定在氟化物暴露和酶诱导下形成的特定脂类。然后，我们将研究蛋白质被含氟物质修饰后所使用的基本细胞应激和防御途径。这个项目还将探索受体结合如何诱导血管生成，这是参与伤口愈合和发展的基本过程，依赖于几种信号脂质的作用。用于分析这些脂质的生物分析方法是世界上少数实验室独有的。这些方法将对我的计划有用，对加拿大科学界来说也是新奇的。*本课程针对环境化学和生物学领域中的不确定关键领域。这项研究将通过了解信号脂质与其他途径协同作用以对抗细胞损伤和维持功能的方式，促进对受环境污染物影响的生物过程的了解。该项目将对环境化学、生物化学和分子生物学领域的学生进行培训。学生将发展批判性思维和科学专业知识，并辅之以强大的沟通和领导能力。结果将被记录在生物活性化学品和脂类生物化学的专业开放获取期刊以及广泛感兴趣的环境化学和生物学期刊上。

We are continuously exposed to environmental contaminants from their presence in our diet and environment. These contaminants are known to manipulate fundamental biological pathways regulated by genes and proteins. However, complete understanding of contaminant fate is lacking because of uncertainty regarding their interaction with lipid signaling molecules. Signaling lipids have long been recognized as vital to an organism's biological processes. My proposed research aims to elucidate the relationship between a class of emerging contaminants, the fluorinated substances, and signaling lipids, to fully appreciate how basic and higher-order cell functions respond and adapt to this exposure. Results gained will enable us to better predict biological outcome after environmental contaminant exposure. ******Research by myself and others has shown that fluorinated substances induce enzymes, modify proteins, and bind to receptors. I hypothesize these processes to be linked to signaling lipid activity. Using cell and animal models routinely used to study protein signaling and patterns of gene regulation, we can measure and place signaling lipids in context with these traditionally studied pathways. We will employ genetic (validation of genes), biochemical (characterizing proteins), and chemical (substances that activate specific targets) approaches to delineate how lipids are affected after contaminant exposure in numerous processes. We will identify specific lipids formed in response to fluorinated substance exposure and enzyme induction. Then, we will examine basic cell stress and defense pathways employed after proteins are modified by fluorinated substances. This program will also explore how receptor binding induces angiogenesis, a fundamental process involved in wound healing and development, which depends on the action of several signaling lipids. The bioanalytical methods used to analyze these lipids are unique to a small number of laboratories worldwide. These methods will be instrumental to my program, and novel to the Canadian scientific community. ******This program addresses critical areas of uncertainty in fields of environmental chemistry and biology. The research will advance knowledge of biological processes affected by environmental contaminants by understanding the ways that signaling lipids act in concert with other pathways to combat cellular insult and maintain function. The program will result in the training of students in fields of environmental chemistry, biochemistry, and molecular biology. Students will develop critical thinking and scientific expertise, complemented by strong communication and leadership skills. Results will be documented in specialized open access journals of bioactive chemicals and lipid biochemistry, as well as broad interest journals of environmental chemistry and biology.*****