Evolutionary genetics of adaptation to toxins in animals

动物适应毒素的进化遗传学

• 批准号: 10714186
• 负责人: Rebecca D. Tarvin
• 金额: $ 40.13万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714186
• 关键词: Affect; Amphibia; Animals; Bacteria; Biological; Biology; Complex; Cystic Fibrosis; Cytochrome P450; Diabetes Mellitus; Disease; Drosophila genus; Drug Delivery Systems; Drug Design; Drug resistance; Epilepsy; Excretory function; Genes; Genetic; Genotype; Goals; Human; Ingestion; Ion Channel; Ion Channel Protein; Link; Medicine; Metabolism; Migraine; Modeling; Mutation; Myotonia; Nervous System; Nervous System Physiology; Neurotoxins; Newts; Nicotine; Organism; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phenotype; Play; Poison; Production; Proteins; Rana; Research; Research Personnel; Resistance; Role; Skin Tissue; System; Tetrodotoxin; Tissues; Toxin; disease phenotype; epibatidine; experimental study; feeding; fitness; gene interaction; genome sequencing; improved; insight; multi drug transporter; nervous system disorder; novel; toad; toxin metabolism; trait; transcriptome sequencing; whole genome

Project Summary/Abstract An important goal in biology is to link genotype with phenotype for traits that affect fitness. The unique adaptations found in animals that sequester neurotoxins are a useful model for understanding the genetic underpinnings of simple and complex traits that are relevant to human medicine. Specifically, neurotoxins target ion channel proteins that are critical for nervous system function. In humans, mutations in single ion channel genes can cause diseases such as epilepsy, myotonia, cystic fibrosis, migraines, and diabetes. However, animals often resist neurotoxins through mutations in these same ion channels, usually without suffering from disease phenotypes. Understanding how diverse organisms fine tune the function of ion channels without causing disease provides important information regarding the genetics of ion channel function and disease. Animals that not only resist but also sequester toxins likely modulate multi-gene pathways underlying toxin metabolism and transport, ultimately leading to selective toxin accumulation into specific tissues at high concentrations. The few known genes involved in toxin sequestration also play critical roles in drug resistance (e.g., multi-drug transporters) and metabolism (cytochrome p450s) in humans. Thus, resistance and sequestration mechanisms parallel pharmaceutical goals to efficiently deliver drugs to specific targets and/or tissues while avoiding drug breakdown or insensitivity. The proposed research aims to further our understanding of the genetic basis of toxin resistance (simple) and sequestration (complex) mechanisms by leveraging state-of-the-art approaches in model and non- model systems. In amphibians, tetrodotoxin resistance has been traced to mutations in ion channels, and tetrodotoxin is thought to be sequestered from symbiotic bacteria. The proposed research will determine whether Harlequin toads obtain toxins from bacteria through bacterial culturing and inoculation experiments. Researchers will then use transcriptome sequencing to determine whether Harlequin toads and Pacific newts modulate production and storage of TTX through specific protein activity in skin tissue. In another project, researchers will identify genes and pathways involved in epibatidine sequestration using toxin-feeding experiments, RNA sequencing, and whole-genome sequencing in poison frogs that can and cannot sequester epibatidine. Finally, researchers will experimentally evolve nicotine sequestration in fruit flies to identify genes and pathways underlying toxin sequestration with unprecedented detail. Understanding the mechanisms used by animals to modulate toxin accumulation and clearance will provide insight into the suite of genes that interact with toxins as they are ingested, transported, stored, or excreted. Given that neurotoxins target critical nervous system proteins and interact with several biological pathways targeted by human medicine, the proposed research has translational implications for pharmacology and the biology of disease.

项目概要/摘要 生物学的一个重要目标是将影响健康的性状的基因型与表型联系起来。独特的 在动物中发现的隔离神经毒素的适应性是了解遗传的有用模型 与人类医学相关的简单和复杂特征的基础。具体来说，神经毒素的目标 对神经系统功能至关重要的离子通道蛋白。在人类中，单离子通道的突变 基因可引起癫痫、肌强直、囊性纤维化、偏头痛和糖尿病等疾病。然而，动物 通常通过这些相同离子通道的突变来抵抗神经毒素，通常不会患上疾病 表型。了解不同的生物体如何微调离子通道的功能而不引起疾病 提供有关离子通道功能和疾病遗传学的重要信息。动物不仅 抵抗但也隔离毒素可能调节毒素代谢和运输的多基因途径， 最终导致高浓度的选择性毒素积累到特定组织中。为数不多的人知道 参与毒素隔离的基因也在耐药性（例如多药物转运蛋白）和 人体新陈代谢（细胞色素 p450）。因此，抵抗和隔离机制并行 制药目标是有效地将药物递送至特定靶点和/或组织，同时避免药物分解 或不敏感。拟议的研究旨在进一步了解毒素抗性的遗传基础 （简单）和封存（复杂）机制，通过利用模型和非模型中最先进的方法 模型系统。在两栖动物中，河豚毒素抗性可追溯到离子通道的突变，并且 河豚毒素被认为是与共生细菌隔离的。拟议的研究将确定是否 丑角蟾蜍通过细菌培养和接种实验从细菌中获取毒素。研究人员 然后将使用转录组测序来确定丑角蟾蜍和太平洋蝾螈是否会调节 通过皮肤组织中特定的蛋白质活性产生和储存 TTX。在另一个项目中，研究人员将 使用毒素喂养实验、RNA 鉴定参与 Epibatidine 隔离的基因和途径 测序，以及毒蛙的全基因组测序，可以和不能隔离皮巴替丁。最后， 研究人员将在果蝇中进行实验进化尼古丁封存，以确定基因和途径 潜在的毒素隔离具有前所未有的细节。了解动物使用的机制 调节毒素积累和清除将提供对与毒素相互作用的一系列基因的深入了解 它们被摄入、运输、储存或排泄。鉴于神经毒素针对关键的神经系统蛋白质 并与人类医学针对的几种生物途径相互作用，拟议的研究具有转化意义 对药理学和疾病生物学的影响。