Evolution, adaptation and structure-function relationships of extinct and extant mammalian hemoglobins: mechanisms of allosteric interactions and their interplay with temperature

将外部环境条件与细胞代谢过程直接联系起来，脊椎动物血红蛋白是精心定制的，以平衡肺部的氧气摄取及其向组织的输送。虽然所有血红蛋白的血红素基团（氧结合位点）是相同的，但珠蛋白的组成在物种之间可以有很大的差异。由珠蛋白链的DNA碱基取代引起的氨基酸组成的看似微小的变化，可以对蛋白质的氧结合特性和对温度的敏感性产生深远的影响。这些改变无疑在哺乳动物占据各种栖息地的能力中发挥了关键作用，但对其精确的分子机制和进化模式知之甚少。这项申请是为了资助对来自灭绝和现存哺乳动物的血红蛋白的新研究，这些哺乳动物专门生活在北极，半水生和地下环境中，特别关注这些呼吸蛋白对温度和其他红细胞配体（二氧化碳，质子，氯离子和某些有机磷酸盐）的氧结合特性。 这些研究构成了基础科学，解决了与这种生物学重要分子的形式，功能和进化有关的基本问题。技术培训将使学生接触最近开发的与呼吸蛋白质的进化、表达和分析有关的技术，传授分子生物学、遗传学和计算方面的技能，培养出在学术界和加拿大迅速发展的以医学为基础的制药和生物技术部门就业的高素质人才。最后，从这项研究计划中获得的见解可能具有重要的应用前景，在血红蛋白为基础的血液替代品的开发与特殊工程的属性。在人们日益关注通过献血传播病毒（艾滋病毒、肝炎、西尼罗河病毒）和其他污染物的情况下，这项技术的出现越来越有吸引力。

Directly linking external environmental conditions with cellular metabolic processes, vertebrate hemoglobins are exquisitely tailored to balance the uptake of oxygen at the lungs and its delivery to the tissues. While the heme groups (the loci for oxygen binding) of all hemoglobins are identical, the globin composition can vary substantially between species. Seemingly small changes in the amino acid composition, resulting from base substitutions with the DNA of the globin chains, can have profound effects on the protein's oxygen-binding characteristics and sensitivity to temperature. These alterations have undoubtedly played a key role in the ability of mammals to occupy a diverse range of habitats, yet little is known regarding their precise molecular mechanisms and mode of evolution. This application is for funds to support novel research on hemoglobins from extinct and extant mammals specialized to life in arctic, semi-aquatic and subterranean environments, focusing specifically on the oxygen binding characteristics of these respiratory proteins in response to temperature and other red cell ligands (carbon dioxide, protons, chloride ions and certain organic phosphates).     These studies constitute basic science that addresses fundamental issues pertaining the form, function and evolution of this biologically important molecule. Technical training will expose students to recently developed techniques relating to the evolution, expression and analyses of respiratory proteins, and impart skills in molecular biology, genetics and computation, producing personnel highly qualified for employment in academia and Canada's rapidly growing medically based pharmaceutical and biotechnology sectors. Finally, insights gained from this research programme may have important applied perspectives in the development of hemoglobin-based blood substitutes with specially engineered properties. The advent of this technology is increasingly attractive in the face of increasing concern over the transmission of viral (HIV, hepatitis, West Nile) and other contaminants via donor blood.