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: 8100125
• 负责人: STEVEN A BENNER
• 金额: $ 29.57万
• 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/8100125
• 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; Florida; Formaldehyde; Fruit; Funding; 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; fly; 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）：如果我们了解它们的结构和历史，那么可以更好地理解生物系统。该提议针对NIAAA和NIEHS，将提供第一个例子，将历史生物学应用于这些机构的感兴趣领域：灵长类动物对环境乙醇的反应的演变。 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. 我们的工作将集中于灵长类动物中酒精脱氢酶甲醛（ADH-ALDH）系统的演变。这些酶形成了两步途径，可从乙醇中产生乙酸。这些酶的基因在与许多酒精相关疾病相关的人类种群中具有遗传变异。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，包括树木，比对，祖先序列以及这些超家族中功能变化的计算分析。这些之后将进行古生物实验，其中将复活来自人类祖先和亲戚的祖先ADH和ALDH，以便在实验室进行研究。底物特异性和动力能力的详细分析将使我们确定我们的祖先是否遵循“避免”，“适应”或“利用”策略，以便在首次出现时管理乙醇，然后随着乙醇的增加和减少灵长类动物的生态系统的增加和减少。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。结果将有助于我们更好地理解模型生物（例如大鼠，苍蝇）收集的数据的人类生物学的含义，后者与人类分开了数亿年。最后，我们将使用还原主义科学，包括蛋白质晶体学，以分子层面描述达尔文流程在管理这种环境基因组动态方面所做的一切。 这项研究将是史蒂文·本纳（Steven Benner）之间的第一次合作，史蒂文·本纳（Steven Benner）启动了实验性古生物学作为一个领域，并在许多生物分子系统[Ben02]和托马斯·赫利（Thomas Hurley）中开发了行星和系统生物学，他全面研究了人类ADHS和ALDHS [HUR01]。除了对该系统进行历史和还原主义分析之外，这项工作还将提供一个范式，显示如何在整个生物医学研究中应用这种组合，因此几乎对人类生物学感兴趣的每个系统产生了影响。 尽管可以更好地理解患病和健康生物学的自然历史，但历史科学很难进入生物医学研究资金的主流。该提案针对NIAAA和NIEHS，寻求资金支持两个实验室之间的合作，以开发一种详细的历史模型，以用于在灵长类动物中饮酒脱氢酶脱氢酶（ADH-aldh）系统的演变，并密切相关的哺乳动物。通过结合自然史和还原主义科学，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的暴露而随着环境状况的变化而共同发展。这将提供第一个将进化分析应用于重要的医学问题的范式，从而鼓励在整个医学研究中应用此类分析，在这种情况下，它们在任何应用范围内都会产生重大影响。