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.

项目摘要 衰老目前是美国慢性病最重要的相关性。一个基本问题 是衰老本身是疾病的因果，还是衰老是衰老的结果 在正常功能的许多复杂系统中，与老年有关的疾病 仅仅是这种失败的最极端形式。从系统生物学的角度来看，这个问题可能是 措辞是引起与衰老相关的复杂功能调节网络中的降解 通过有限的集中组件/节点，或者是否与衰老相关的下降是由 整个网络中的异质失败，然后导致不可避免的脆弱交叉 临界点。我们旨在使用特定年龄变化的全面网络分析来检验这些假设 在基因表达和蛋白质丰度中，使用线虫秀丽隐杆线虫作为模型系统。 具体而言，我们的目的是（1）确定基因调节网络的年龄特异性变化 分辨率，定义与寿命和中央特别相关的子组件 HealthSpan措施，（2）使用自然遗传变异系统地扰动年龄特异性 监管网络以确定监管结构和因果关系 网络和（3）关于特定年龄调节的新兴结构的测试功能假设 网络并将网络属性与寿命的个体变化相关联，使用敲除和过度 表达构造。我们的方法具有三个独特的元素。首先，我们使用微流体技术来 图像基因表达报道在细胞和亚细胞的分辨率上，允许我们的网络 特定于组织的方法。因为这种方法是高通量和无损的，所以这些成像 实验还将告知网络的时间动态。其次，我们使用自然遗传变异 再加上整个基因组测序到首先扰动网络结构，然后绘制遗传因果关系， 从而确定整个网络的方向性。第三，我们达到了这一高水平 通过对已对样品进行分类的样品进行大量分析分析（极端QTL）来映射精度 使用定制设计的微流体设备的差异基因表达，寿命和健康范围的生物标志物。 这些方法将使我们能够重建组织特异性年龄相关的调节网络，以 检查并在功能上验证网络结构和功能变化的紧急特性 衰老，并将这些变化与长寿变化相结合。