Modulation of membrane architecture and function by physiologically relevant and toxic ions

有毒金属是加拿大及其他地区自然科学和工程领域日益关注的重大问题的核心。事实上，有毒金属的离子混合物通过仍鲜为人知的机制扰乱了生理。根据我对生物膜结构和功能的长期研究兴趣，这项建议解决了离子和有毒金属对膜的影响。比较了必需离子Na+、K+、Ca++与常见污染物Cd++、Hg++的影响。离子组合很重要，因为人体暴露在污染物的混合物中，这可能会增加它们的影响。这些离子的毒性不同，因为Cd++被报道为野生动物的一个问题，而汞++更多的是对家养动物的关注。离子-膜相互作用在四个方面进行了研究： I)表面离子结合：利用一种新的分析方法，我们发现汞离子优先选择带负电荷的磷脂酰丝氨酸(PS)，而Cd++与两性离子磷脂酰乙醇胺相互作用更强。 Ii)对膜动力学的影响：有毒二价离子的相互作用往往会降低膜的流动性和增加膜的通透性，这两者都会影响细胞的功能。从脂类组成和离子混合物的使用两个方面进行了综合分析。 Iii)对膜组织的影响：离子可以影响脂相行为并诱导脂类聚集，如钙和PS的相互作用所见，由此产生的斑块与蛋白质结合。 四)对红细胞和提取物的影响：模型系统将与生物提取物和血细胞进行比较。已有报道称，Cd++和Hg++对红细胞的特征盘状形状有影响，但不是以浓度依赖的方式改变，也不是在暴露于离子混合物后改变。 这项拟议的工作对于全面研究离子对生物膜的影响具有重要意义。更好地理解基本的生物学原理可能有助于发现更好的方法来控制污染物对野生动物、牲畜乃至公共健康的影响。

Toxic metals are at the core of significant and growing concerns to the Natural Sciences and Engineering fields in Canada and beyond. Indeed, ion mixtures of toxic metals disrupt physiology via mechanisms that remain poorly understood. In accord with my long term research interest in the structure and function of biomembranes, this proposal addresses the impact of ions and toxic metals on membranes. The impact of essential ions Na+, K+ and Ca++ is compared with the common pollutants Cd++ and Hg++. Ion combinations are important since the human body is exposed to a mix of pollutants which may increase their effects. These ions differ in their toxicity as Cd++ was reported as a problem for wildlife whereas Hg++ is more a concern for domestic animals. Ion-membrane interactions are studied in four areas: i) ion binding to the surface: Using a novel assay we have shown that Hg++ preferred negatively charged phosphatidylserine (PS) whereas Cd++ interacted stronger with zwitterionic phosphatidylethanolamines. ii) impact on membrane dynamics: The interaction of toxic divalent ions often decreased membrane fluidity and increased of membrane permeability which both effect cellular function. A comprehensive analysis in terms of lipid composition and the use of ion mixtures is proposed. iii) impact on membrane organization: Ions can impact the lipid phase behavior and induce clustering of lipids as seen for the interactions of Ca++ and PS whereby resulting patches bind proteins. iv) impact on red blood cells and extracts: Model systems will be compared with biological extracts and blood cells. Changes of the characteristic discoidal shape of red blood cells by Cd++ and Hg++ have been reported but not in a concentration dependant manner or after exposure to ion mixtures. The proposed work is significant as a comprehensive investigation of the impact of ions on biomembranes. A better understanding of the basic biological principles may help to uncover better means to control the effects of pollutants on wildlife, livestock and indeed public health.