Alcohol Metabolism,Primate Evolution and Paleogenetics. An Inclusive Paradigm

酒精代谢、灵长类动物进化和古遗传学。

• 批准号: 7878547
• 负责人: STEVEN A BENNER
• 金额: $ 30.76万
• 依托单位: FOUNDATION FOR APPLIED MOLECULAR EVOLUTN
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-25 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7878547
• 关键词: Acetaldehyde; Acetates; Adopted; Alcohol dehydrogenase; Alcoholism; Alcohols; All-Trans-Retinol; Amino Acids; Angiosperms; Animal Model; Animals; Appearance; Area; Automobile Driving; Beer; Behavior; Bioinformatics; Biology; Biomedical Research; Biotechnology; Carbohydrates; Carbon; Cereals; Chemistry; Collaborations; Computer Simulation; Contracts; Crystallography; Data; Databases; Disease; Ecosystem; Energy-Generating Resources; Environment; Environmental Exposure; Enzyme Gene; Enzymes; Ethanol; Ethanol Metabolism; Evolution; Exposure to; Family; Fatty Acids; Fermentation; Figs - dietary; Florida; Formaldehyde; Fruit; Funding; Future; Gene Proteins; Genes; Genetic Polymorphism; Genetic Variation; Genome; Genomics; Glutathione; Homo sapiens; Housing; Human; Human Biology; Indiana; Individual; Institutes; Joints; Kidney; Kinetics; Knowledge; Laboratories; Laboratory Study; Libraries; Life; Life Style; Liver; Mainstreaming; Mammals; Marsupialia; Measures; Medical; Medical Research; Methods; Mitochondria; Modeling; Molecular; Molecular Biology; Molecular Evolution; Movement; Mutation; National Institute of Environmental Health Sciences; National Institute on Alcohol Abuse and Alcoholism; Natural History; Nucleotides; Organic Chemistry; Oxidation-Reduction; Oxidoreductase; Paleontology; Pathway interactions; Pattern; Pongidae; Population; Primates; Process; Property; Proteins; Rattus; Reaction; Recording of previous events; Relative (related person); Research; Research Personnel; Resources; Retinal; Science; Sequence Alignment; Site; Specificity; Steroids; Sterols; Structure; Substrate Specificity; System; Systems Analysis; Systems Biology; Technology; Testing; Time; Tissues; Toxic Environmental Substances; Trees; United States National Institutes of Health; Variant; Vertebrates; Vitamins Nutrition; Wine; Work; Yeasts; alcohol response; aldehyde dehydrogenases; base; biological systems; cDNA Library; combinatorial chemistry; environmental change; gastrointestinal system; human disease; innovation; interest; meetings; oxidation; pressure; prevent; reconstitution; research study; response; tool

DESCRIPTION (provided by applicant): It is axiomatic that biological systems can be better understood if we understand both their structure and their histories. This proposal, directed towards the NIAAA and NIEHS, will provide the first example where historical biology is applied to an area of interest to these institutes: the evolution of the response of primates to environmental ethanol. Using an innovative combination of molecular evolution, paleontology, organic chemistry, kinetics, molecular biology, biotechnology, and crystallography, this research will yield a model that describes, from the biomolecule to the pathway, the adaptive response of primates, including humans, as they encountered, managed, and ultimately exploited a new environmental toxin, ethanol, over the past 100 million years. Our work will focus on the evolution of the alcohol dehydrogenase-aldehyde dehydrogenase (ADH-AlDH) system in primates. These enzymes form a two-step pathway that yields acetate from ethanol. Genes for these enzymes hold genetic variation in human populations that correlates with many alcohol-related diseases. We will first collect primate sequences to enrich the evolutionary models for these two superfamilies of proteins, including trees, alignments, ancestral sequences, and computational analyses of functional change within these superfamilies. These will be followed by paleogenetic experiments, where ancestral ADHs and AlDHs from human ancestors and relatives will be resurrected for study in the laboratory. Detailed analyses of substrate specificity and kinetic power will let us determine whether our ancestors followed "avoidance", "accommodation", or "utilization" strategies to manage ethanol when it first emerged, and thereafter as ethanol increased and decreased in the ecosystems of primates, until the present. These will be supplemented by analyzing the evolution of the "systems biology" properties of the system. The results will help us better understand the meaning in human biology of data collected in model organisms (e.g. rat, fly), which are separated from humans by hundreds of millions of years. Finally, we will use reductionist science, including protein crystallography, to describe at a molecular level what Darwinian processes did to manage this environment-genomics dynamic. This research will be the first collaboration between Steven Benner, who initiated experimental paleogenetics as a field and has developed planetary and systems biology in many biomolecular systems [Ben02], and Thomas Hurley, who has comprehensively studied human ADHs and AlDHs [Hur01]. In addition to producing a combined historical and reductionist analysis of this system, this work will provide a paradigm showing how this combination can be applied throughout biomedical research, and therefore have an impact on nearly every system of interest to human biology. Although it is axiomatic that diseased and healthy biology can be better understood if we understand its natural history, historical science has had difficulty entering the mainstream of biomedical research funding. This proposal, directed towards the NIAAA and NIEHS, seeks funding to support a collaboration between two laboratories to develop a detailed historical model for the evolution of the alcohol dehydrogenase-aldehyde dehydrogenase (ADH-AlDH) system in primates and closely related mammals. By combining natural history and reductionist science, the work will show how the substrate specificities and catalytic activities of these two enzymes co-evolved in response to changing environmental conditions, as the exposure of this environmental toxin changed. This will provide the first paradigm applying evolutionary analysis to an important medical problem, thereby encouraging the application of such analyses throughout medical research, where they are expected to have significant impact wherever they are applied.

描述（由申请人提供）：不言而喻的是，如果我们了解生物系统的结构和历史，就可以更好地理解它们。这项针对 NIAAA 和 NIEHS 的提案将提供第一个例子，将历史生物学应用于这些机构感兴趣的领域：灵长类动物对环境乙醇反应的进化。这项研究将分子进化、古生物学、有机化学、动力学、分子生物学、生物技术和晶体学的创新结合起来，产生一个模型，从生物分子到途径，描述灵长类动物（包括人类）的适应性反应。在过去的一亿年里，人类遇到、管理并最终利用了一种新的环境毒素——乙醇。 我们的工作将重点关注灵长类动物中乙醇脱氢酶-乙醛脱氢酶（ADH-AlDH）系统的进化。这些酶形成了从乙醇产生乙酸的两步途径。这些酶的基因在人群中存在遗传变异，这些变异与许多酒精相关疾病相关。我们将首先收集灵长类动物序列以丰富这两个蛋白质超家族的进化模型，包括树、比对、祖先序列以及这些超家族内功能变化的计算分析。随后将进行古遗传学实验，其中来自人类祖先和亲戚的祖先 ADH 和 AlDH 将被复活以供实验室研究。对底物特异性和动能的详细分析将让我们确定我们的祖先在乙醇首次出现时是否遵循“回避”、“适应”或“利用”策略来管理乙醇，此后随着乙醇在灵长类动物生态系统中的增加和减少，直到现在。这些将通过分析系统的“系统生物学”特性的演变来补充。这些结果将帮助我们更好地理解从与人类相隔数亿年的模型生物（例如老鼠、苍蝇）中收集的数据在人类生物学中的意义。最后，我们将使用还原论科学，包括蛋白质晶体学，在分子水平上描述达尔文过程如何管理这种环境基因组动态。 这项研究将是 Steven Benner 和 Thomas Hurley 之间的首次合作，Steven Benner 开创了实验古遗传学领域，并在许多生物分子系统中发展了行星和系统生物学 [Ben02]，而 Thomas Hurley 则全面研究了人类 ADH 和 AlDH [Hur01]。除了对该系统进行历史和还原论的综合分析之外，这项工作还将提供一个范式，展示如何将这种组合应用于整个生物医学研究，从而对人类生物学感兴趣的几乎所有系统产生影响。 尽管如果我们了解其自然历史，就可以更好地理解患病和健康的生物学，这是不言而喻的，但历史科学很难进入生物医学研究资助的主流。这项针对 NIAAA 和 NIEHS 的提案寻求资金支持两个实验室之间的合作，以开发灵长类动物和密切相关的哺乳动物中乙醇脱氢酶-乙醛脱氢酶 (ADH-AlDH) 系统进化的详细历史模型。通过结合自然历史和还原论科学，这项工作将展示这两种酶的底物特异性和催化活性如何随着这种环境毒素暴露的变化而共同进化以响应不断变化的环境条件。这将提供第一个将进化分析应用于重要医学问题的范例，从而鼓励在整个医学研究中应用此类分析，无论在何处应用，它们都有望产生重大影响。