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

我们在饮食和环境中不断接触到环境污染物。已知这些污染物操纵由基因和蛋白质调节的基本生物途径。然而，由于污染物与脂质信号分子相互作用的不确定性，对污染物命运的全面了解尚不充分。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兴污染物，氟化物质和信号脂质之间的关系，以充分了解基本和高阶细胞功能如何响应和适应这种暴露。获得的结果将使我们能够更好地预测环境污染暴露后的生物学结果。******我和其他人的研究表明，含氟物质会诱导酶，修饰蛋白质，并与受体结合。我假设这些过程与脂质活性信号有关。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，我们可以在这些传统研究途径的背景下测量和放置信号脂质。我们将采用遗传（基因验证）、生化（表征蛋白质）和化学（激活特定靶标的物质）方法来描述在众多过程中暴露于污染物后脂质是如何受到影响的。我们将确定在氟化物质暴露和酶诱导下形成的特定脂质。然后，我们将研究蛋白质被氟化物质修饰后的基本细胞应激和防御途径。该计划还将探讨受体结合如何诱导血管生成，这是一个涉及伤口愈合和发展的基本过程，它取决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所独有的。这些方法对我的项目很有帮助，对加拿大科学界来说也是新奇的。******该计划解决了环境化学和生物学领域不确定的关键领域。这项研究将通过了解信号脂质与其他途径协同对抗细胞损伤和维持功能的方式，推进受环境污染物影响的生物过程的知识。该项目将培养环境化学、生物化学和分子生物学领域的学生。学生将培养批判性思维和科学专业知识，并辅以较强的沟通和领导能力。结果将被记录在生物活性化学和脂质生物化学的专业开放获取期刊上，以及环境化学和生物学的广泛兴趣期刊。*****

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.*****