Genetic and Genomic Analysis of Starvation Resistance in C. elegans

线虫饥饿抗性的遗传和基因组分析

• 批准号: 10272834
• 负责人: Larry Ryan Baugh
• 金额: $ 30.46万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10272834
• 关键词: Acute; Affect; Aging; Biochemical; Biological Assay; Caenorhabditis elegans; Cancer Etiology; Chromatin Structure; Clinical; Complex; Data; Development; Diabetes Mellitus; Disease; Famines; Food; Foundations; Functional disorder; Gene Expression; Gene Expression Regulation; Gene Family; Genes; Genetic; Genetic Epistasis; Genomics; Goals; Growth; Growth and Development function; Health; Histone H1; Histones; Human; Insulin; Insulin Receptor; Investigation; Larva; Literature; Lobular Neoplasia; Longevity; MAP Kinase Gene; Malignant Neoplasms; Measures; Mediating; Metabolism; Modeling; Modification; Molecular; Nutrient; Nutritional; Orthologous Gene; Outcome; PTEN gene; PTEN protein; Pathway interactions; Population; Prevention strategy; Protein phosphatase; Proteins; Proto-Oncogenes; Public Health; Publishing; Regulation; Regulator Genes; Reproduction; Research; Resistance; Role; Signal Transduction; Starvation; System; Testing; Therapeutic Intervention; Transcriptional Regulation; Tumor Suppressor Proteins; Variant; Work; ZFY protein; base; deep sequencing; gene repression; high dimensionality; human disease; innovation; member; mortality; novel; protein function; resistance mechanism; trait; transcription factor; tumor

PROJECT SUMMARY By governing growth and quiescence, nutrient-responsive pathways are central to cancer, diabetes and aging. The function of these pathways in starvation informs understanding of their dysfunction in disease, but their fundamental role in starvation is not well understood. The premise of this proposal is that multiple tumor sup- pressors are known to promote starvation resistance, but their regulatory relationships and effector mecha- nisms are unclear. The long-term goal of this project is to elucidate the genetic foundation and molecular mechanisms of starvation resistance in C. elegans as a model for human disease. Worms are an ideal model since they thrive in feast and famine with remarkable ability to endure starvation. Genes known to promote starvation resistance in C. elegans (eg, daf-18/PTEN, daf-16/FoxO, lin-35/Rb, hlh-30/TFEB and aak-2/AMPK) have conserved function in suppressing tumors, regulating metabolism, and promoting longevity. However, significant gaps in understanding remain. Preliminary studies show that inhibition of PI3K signaling does not account for the effect of DAF-18/PTEN on starvation resistance. They show that DAF-18/PTEN's protein- phosphatase activity promotes starvation resistance, and they identify a novel protein target. Preliminary re- sults also suggest that DAF-16/FoxO and LIN-35/Rb regulate histone variants to mediate nutritional control of chromatin structure and gene regulation. They also demonstrate the efficacy of an innovative population- sequencing approach for analysis of quantitative traits, and they identify novel genes affecting natural variation in starvation resistance. These include modifiers of insulin/IGF signaling and a conserved but uncharacterized transcription factor. The central hypothesis of this proposal is that a conserved network of tumor suppressors and proto-oncogenes governs starvation resistance through a variety of effector mechanisms. The objective of this proposal is to expand understanding of this network by identifying novel components, regulatory interac- tions, and effector mechanisms. The central hypothesis is supported by strong preliminary data and the litera- ture. It will be tested with the following three aims: 1) Identify DAF-18/PTEN targets that promote starvation resistance, 2) Identify gene regulatory mechanisms that mediate adaptation to starvation, and 3) Identify genes and mechanisms that contribute to natural variation in starvation resistance. Genetic, genomic and biochemical approaches will be used to complete these aims. This work is technically innovative for using population se- quencing to leverage the power of deep sequencing for statistical genetics, and for using gene expression as a high-dimensional trait for epistasis analysis. It is intellectually innovative for hypothesizing a novel regulatory relationship between clinically important tumor suppressors. The contributions of the proposed work will be identification of novel components, regulatory interactions and effector mechanisms of the regulatory network governing starvation resistance. These contributions will be significant because starvation resistance is a fun- damental trait intimately related to human health and disease, and genes under investigation are conserved.

项目概要 通过控制生长和静止，营养反应途径对于癌症、糖尿病和衰老至关重要。 这些途径在饥饿中的功能有助于了解它们在疾病中的功能障碍，但它们的 饥饿的根本作用尚不清楚。该提议的前提是多种肿瘤支持 众所周知，升压因子可以促进饥饿抵抗，但它们的调节关系和效应机制 主义尚不明确。该项目的长期目标是阐明遗传基础和分子机制 线虫作为人类疾病模型的饥饿抵抗机制。蠕虫是一个理想的模型 因为它们在盛宴和饥荒中都能茁壮成长，具有非凡的忍饥能力。已知促进的基因 线虫的饥饿抗性（例如 daf-18/PTEN、daf-16/FoxO、lin-35/Rb、hlh-30/TFEB 和 aak-2/AMPK） 具有抑制肿瘤、调节代谢、延年益寿等功能。然而， 理解上仍然存在重大差距。初步研究表明，抑制 PI3K 信号传导不会 解释 DAF-18/PTEN 对饥饿抵抗的影响。他们表明 DAF-18/PTEN 的蛋白质- 磷酸酶活性可促进饥饿抵抗，并且他们确定了一种新的蛋白质靶点。初步重新 结果还表明 DAF-16/FoxO 和 LIN-35/Rb 调节组蛋白变异以介导营养控制 染色质结构和基因调控。他们还展示了创新群体的功效—— 用于分析数量性状的测序方法，并识别影响自然变异的新基因 在抗饥饿方面。这些包括胰岛素/IGF信号传导的修饰剂和保守但未表征的 转录因子。该提案的中心假设是肿瘤抑制基因的保守网络 原癌基因通过多种效应机制控制饥饿抵抗。的目标 该提案旨在通过识别新的组成部分、监管互动来扩大对该网络的理解 系统蒸发散和效应机制。中心假设得到了强有力的初步数据和文献的支持 确实。它将针对以下三个目标进行测试：1）识别促进饥饿的 DAF-18/PTEN 目标 抗性，2) 识别介导适应饥饿的基因调控机制，以及 3) 识别基因 以及有助于抗饥饿性自然变异的机制。遗传学、基因组学和生物化学 将使用各种方法来完成这些目标。这项工作在技术上具有创新性，可以利用人口统计数据 测序利用深度测序的力量进行统计遗传学，并使用基因表达作为 用于上位分析的高维特征。假设一种新颖的监管方式在智力上具有创新性 临床上重要的肿瘤抑制因子之间的关系。拟议工作的贡献将是 识别调控网络的新成分、调控相互作用和效应机制 控制饥饿抵抗力。这些贡献将是重要的，因为抗饥饿是一种有趣的 与人类健康和疾病密切相关的基本特征和正在研究的基因是保守的。