Systems variation underlying the genetics of aging

衰老遗传学背后的系统变异

• 批准号: 9369804
• 负责人: Hang Lu
• 金额: $ 49.5万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9369804
• 关键词: Address; Age; Aging; Bayesian Method; Biological; Biological Markers; Biological Models; Biological Process; Biology of Aging; Caenorhabditis elegans; Chronic Disease; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Coupled; Coupling; Custom; Disease; Elements; Etiology; Failure; Future; Gene Expression; Gene Proteins; Genes; Genetic; Genetic Variation; Genomic approach; Genomics; Grant; Health; Human; Image; Incidence; Individual; Intervention; Knock-out; Link; Longevity; Maps; Measurement; Measures; Medicine; Methods; Microfluidic Microchips; Microfluidics; Molecular; Nematoda; Outcome; Pathway Analysis; Pattern; Phenotype; Property; Quality of life; Quantitative Trait Loci; Regulator Genes; Reporter; Research; Resolution; Risk Factors; Sampling; Structure; System; Systems Analysis; Systems Biology; Techniques; Technology; Testing; Time; Tissue-Specific Gene Expression; Tissues; United States; Variant; age related; base; design; drug development; experimental study; frailty; functional genomics; genetic approach; genome sequencing; genomic data; healthy aging; high throughput technology; imaging modality; innovation; knock-down; novel; overexpression; phrases; theories; transcription factor; whole genome

PROJECT SUMMARY Aging is currently the most important correlate of chronic illness in the United States. A fundamental question is whether aging is itself causal of disease or if aging is the result of generalized accumulation of failures among the many complex systems that underlie normal function, with the diseases associated with old age simply being the most extreme form of this failure. From a systems biology perspective, this question can be phrased as whether the degradation in complex functional regulatory networks associated with aging is caused by a limited set of central components/nodes or whether aging-associated decline is generated by heterogeneous failure across the entire network which then leads to an inevitable crossing of a critical frailty threshold. We aim to test these hypotheses using a comprehensive network analysis of age-specific changes in gene expression and protein abundance using the nematode Caenorhabditis elegans as a model system. Specifically, we aim to (1) determine age-specific changes in the gene regulatory network at a cellular resolution, defining subcomponents that are specifically correlated with lifespan and central healthspan measures, (2) use natural genetic variation to systematically perturb the age-specific regulatory network in order to determine the regulatory structure and causal connections within the network, and (3) test functional hypotheses about the emergent structure of the age-specific regulatory network and relate network properties to individual variation in longevity, using knockouts and over- expression constructs. Our approach has three unique elements. First, we use microfluidic techniques to image gene expression reporters at a cellular and sub-cellular level of resolution, allowing our network approaches to be tissue specific. Because this approach is high-throughput and nondestructive, these imaging experiments will also inform the temporal dynamics of the networks. Second, we use natural genetic variation coupled with whole genome sequencing to first perturb network structure and then map genetic causation, thereby allowing directionality across the network to be established. Third, we achieve this high level of mapping precision by conducting bulk segregant analysis (extreme QTL) on samples that have been sorted for differential gene expression, longevity and healthspan biomarkers using custom-designed microfluidic devices. These approaches will allow us to reconstruct the tissue-specific age-associated regulatory network, to examine and functionally validate emergent properties of changes in network structure and function during aging, and to couple these changes to individual variation in longevity.

项目概要 目前，老龄化是美国慢性病最重要的相关因素。一个基本问题 是衰老本身是疾病的原因还是衰老是普遍失败累积的结果 在构成正常功能基础的许多复杂系统中，以及与老年相关的疾病 只是这种失败的最极端形式。从系统生物学的角度来看，这个问题可以 表述为是否导致与衰老相关的复杂功能调节网络的退化 由一组有限的中央组件/节点或是否由老化相关的衰退产生 整个网络中的异构故障不可避免地会导致关键弱点的交叉 临界点。我们的目标是通过对特定年龄变化的全面网络分析来检验这些假设 使用线虫秀丽隐杆线虫作为模型系统来研究基因表达和蛋白质丰度。 具体来说，我们的目标是（1）确定细胞基因调控网络的年龄特异性变化。 分辨率，定义与寿命和中心具体相关的子组件 健康跨度测量，（2）利用自然遗传变异系统地扰乱特定年龄的 监管网络，以确定监管结构和内部因果关系 网络，以及（3）测试有关特定年龄监管的新兴结构的功能假设 网络并将网络属性与寿命的个体差异联系起来，使用淘汰赛和过度 表达结构。我们的方法具有三个独特的要素。首先，我们使用微流控技术 在细胞和亚细胞分辨率水平上对基因表达记者进行成像，使我们的网络 方法具有组织特异性。由于这种方法具有高通量和非破坏性，因此这些成像 实验还将揭示网络的时间动态。其次，我们利用自然遗传变异 结合全基因组测序，首先扰乱网络结构，然后绘制遗传因果关系图， 从而允许建立整个网络的方向性。第三，我们达到了这个高水平 通过对已分选的样品进行批量分离分析（极端 QTL）来提高作图精度 使用定制设计的微流体装置进行差异基因表达、寿命和健康寿命生物标志物。 这些方法将使我们能够重建组织特异性的年龄相关调节网络， 检查并在功能上验证网络结构和功能变化的紧急属性 衰老，并将这些变化与寿命的个体差异联系起来。