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Doctoral Dissertation Research: Investigating Genomic and Expression-level Adaptations for Detoxification in Primates

博士论文研究：研究灵长类动物解毒的基因组和表达水平适应性

基本信息

批准号：
1919857
负责人：
Anthony Tosi
金额：
$ 3万
依托单位：
Kent State University
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1919857&HistoricalAwards=false
关键词：
Doctoral Dissertation Research Investigating Genomic

项目摘要

Cyanide is a poison that is common among plants and toxic to most animals. Nonetheless, three species of bamboo lemur focus most of their feeding time on various parts of Malagasy giant bamboo, which exposes the lemurs to 12-50 times their estimated lethal dose of cyanide on a daily basis. This project will examine the underlying physiology and genomics of cyanide detoxification in bamboo lemurs. In addition to addressing the decades-old puzzle of how these lemurs are able to consume high levels of cyanide, this study may inform the development of therapies, antidotes, or prophylactics to cyanide exposure in humans. During the course of this work, the PI and co-PI will invite and recruit undergraduates from Kent State University's McNair Scholars Program, whose mission is to help first-generation, low-income undergraduates matriculate to a doctoral degree program. The co-PI will also utilize close ties with Northeast Ohio's public libraries and schools to present this project to students and the general public.The central questions of this study focus on known routes of cyanide detoxification among mammals. Low doses of the poison can be metabolized by a variety of conserved mechanisms, foremost among which is a pathway that uses sulfurtransferase enzymes. The limiting factors for this mechanism appear to be relative expression levels for these enzymes and the availability of sulfur-donor molecules (e.g., thiosulfate). Therefore, the first working hypothesis of this study is that H. aureus has adapted to detoxify its highly cyanogenic diet through positive selection on genes involved in the metabolism of sulfur or sulfur-containing amino acids. This hypothesis will be tested by assembling and mining a reference-quality genome for H. aureus and comparing it to data taken from a proposed genome assembly for Lemur catta, the most closely related species of dietary generalist. It is further hypothesized that H. aureus detoxifies its high levels of circulating cyanide through adaptive changes to the composition of the bloodstream. This second hypothesis will be tested by transcriptomic and metabolomic methods in order to compare the expression profiles and thiosulfate levels, respectively, of free-ranging H. aureus and captive L. catta. Together, these methods will examine adaptive changes in the H. aureus genome, as well as the whole-blood transcriptome and metabolome, which are related to the exceptional cyanide tolerance of this species.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

氰化物是一种在植物中常见的毒物，对大多数动物都是有毒的。尽管如此，三种竹狐猴的大部分觅食时间都集中在马达加斯加巨型竹子的不同部位，这使得狐猴每天接触到估计致命剂量的氰化物12-50倍。这个项目将研究竹狐猴氰化物解毒的潜在生理学和基因组学。除了解决这些狐猴如何能够消耗高水平的氰化物这一数十年来的谜题外，这项研究还可能为人类氰化物暴露疗法、解毒剂或预防性药物的开发提供信息。在这项工作中，PI和共同PI将邀请和招募肯特州立大学麦克奈尔学者项目的本科生，该项目的使命是帮助第一代低收入本科生进入博士学位项目。联合PI还将利用与俄亥俄州东北部公共图书馆和学校的密切联系，向学生和公众介绍这一项目。这项研究的中心问题集中在哺乳动物中氰化物解毒的已知途径上。低剂量的毒物可以通过各种保守的机制进行代谢，其中最重要的是使用硫磺转移酶的途径。这一机制的限制因素似乎是这些酶的相对表达水平和硫供体分子(如硫代硫酸盐)的可用性。因此，这项研究的第一个工作假设是，金黄色葡萄球菌通过对与硫或含硫氨基酸代谢有关的基因进行正选择，已经适应了对其高氰化性食物的解毒。这一假说将通过组装和挖掘金黄色葡萄球菌的参考质量基因组，并将其与拟议中的狐狸基因组组装数据进行比较来验证这一假设，狐狸是最接近的饮食多面手物种。进一步的假设是，金黄色葡萄球菌通过对血液成分的适应性变化来解毒其高水平的循环氰化物。第二个假设将通过转录和代谢组学方法进行验证，以便分别比较自由放养的金黄色葡萄球菌和圈养的金黄色葡萄球菌的表达谱和硫代硫酸盐水平。这些方法将共同检查金黄色葡萄球菌基因组的适应性变化，以及与该物种特殊的氰化物耐受性有关的全血转录组和代谢组。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。