Bio-computational Image Analysis to Define Indicators of C. elegans Healthspan

描述(由申请人提供)：现代老龄化研究的一个中心目标是寻找创新的方法来确定最大化人类健康寿命的分子策略。尽管秀丽线虫等模型系统已经被用来定义数百个影响寿命的基因，但还没有对延长健康寿命的突变进行特定和定向的基因筛查。阻碍使用强大的遗传方法来解决这个极其重要的问题的一个主要原因是，没有可以在基因筛查中广泛使用的快速得分的健康寿命指标。在这里，我们提出了一个合作项目，其中我们结合了线虫衰老生物学的专业知识和复杂的、最先进的图像处理能力。我们的目标是开发运动分析程序，测量和报告与年龄相关的运动能力下降的多个方面，建立一个易于评分和广泛使用的健康跨度量表。我们的具体目标是：目标1.开发图像分析方案，快速、可靠地测量线虫在液体中运动的多个参数/指标。目的II.使用自动化分析对野生型和典型健康跨度突变体中与年龄相关的游泳下降进行评分。目的III.调整和优化游泳成像方案以高通量分析健康跨度。通过执行我们的合作项目和仔细的控制和训练集，我们将揭示与年龄相关的运动能力下降的生物学方面的大量信息。我们将描述多个量化参数，这些参数表明减速在种群和个体动物中是如何发生的；我们可能会为年龄较差的动物和年龄较好的动物定义特定的标准；我们将详细描述胰岛素信号如何提高运动健康寿命；我们将调查影响多个过程的具有代表性的长寿基因组，以确定哪些基因也具有健康寿命效应。从长远来看(超出本应用的范围)，我们将使用开发的健康寿命评分能力来确定延长健康寿命的遗传和药物方法。我们计划将这个评分系统提供给线虫研究社区，用于衰老研究和其他应用。

DESCRIPTION (provided by applicant): A central goal of modern aging research is to seek innovative ways to identify molecular strategies to maximize human healthspan. Although model systems such as C. elegans have been exploited to define hundreds of genes affecting longevity, specific and directed genetic screens for mutations that extend healthspan have not yet been pursued. A major reason for the roadblock in unleashing powerful genetic approaches to this profoundly important problem is that there are no rapidly scored indicators of healthspan that can be used broadly in genetic screens. Here we propose a collaborative project in which we combine expertise in C. elegans aging biology with sophisticated, state-of-the-art image processing capability. Our goal is to develop motion analysis programs that measure and report multiple aspects of age-related locomotion decline, establishing an easily scored and broadly useful healthspan scale. Our specific aims are: Aim I. To develop image analysis protocols to rapidly and reliably measure multiple parameters/indicators of C. elegans locomotion in liquid. Aim II. To use automated analysis to score age-related swimming decline in wild type and exemplary healthspan mutants. Aim III. To adapt and optimize swimming imaging protocols for high throughput analysis of healthspan. By executing our collaborative project with careful controls and training sets, we will reveal a considerable amount about the biology of age-related locomotory decline. We will describe multiple quantitative parameters that indicate how slow-down transpires both in populations and in individual animals; we may define specific criteria for animals that age poorly vs. those that age well; we will describe in detail how insulin signaling boosts locomotory healthspan; we will survey representative groups of longevity genes that affect multiple processes to determine those that also confer healthspan effects. Over the long term (beyond the scope of this application), we will use the developed healthspan scoring capacity to identify genetic and pharmacological approaches toward extending healthspan. We plan to make this scoring system available to the C. elegans research community for use in aging studies and additional applications.