RoL: FELS: EAGER Rules of lifespan determination and buffering from lifelong spatiotemporal activity of key aging pathways.

该项目将开发必要的工具和数据，以准确预测基因活动对环境条件（如食物摄入或压力暴露）的反应的寿命。基因和环境是如何决定一个人的具体寿命结果的，目前还不完全清楚。例如，众所周知，减少卡路里或减少氧化应激可以延长寿命，但仅凭这些信息精确预测寿命是不可能的。考虑到研究人类衰老的困难，秀丽隐杆线虫（Caenorhabditis elegans）将被用作连接已知影响衰老的特定基因活动的模型。将建立环境、基因和寿命之间关系的数学模型，揭示哪些基因和环境在决定衰老和寿命方面最重要，并使寿命预测成为可能。这些信息将用于未来的工作，重点是这些预测是否可以扩展到其他生物体，并最终扩展到人类。通过这项工作，两名研究生和一名博士后将接受跨学科的培训。此外，该项目还将支持一项针对高中生的拉丁裔STEM计划。该项目的主要目标是开发一个实验和分析管道，从而能够建立模型生物秀丽隐杆线虫的寿命确定规则。将开发基于关键衰老途径的终身活动来预测个人寿命的数学和统计模型。该研究测试了关键基因活动的可变性（由于生物噪声或环境或遗传扰动）是否会传播到寿命的可变性。为了解决这个问题，将开发一种微流控平台，可以监测多个个体的整个生命周期，同时通过内源性荧光报告来量化关键衰老途径的活性。该提议的平台将允许数据配对，其中单个个体水平的基因活动可以与其寿命配对。能够同时定量分析体内基因活性和组合环境扰动的实验工具将被开发出来。这些工具依赖于微流体、计算机视觉、自动化和由CRISPR设计的新的报告菌株，以跟踪内源性调控控制下的基因活性。获得的数据集将用于推导数据驱动的数学模型，该模型描述基因活动的随机动力学及其下游表型结果：寿命。新的统计技术将与数学模型相结合，以推断种群内的表型异质性和稳健性。将为两名研究生和一名博士后研究员提供跨学科培训，该奖项将支持一个旨在扩大拉丁裔高中生参与科学的教育项目。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

This project will develop tools and data necessary to accurately predict lifespan from the activity of genes that respond to environmental conditions such as food intake or stress exposure. It is not fully understood how genes and the environment determine an individual's specific longevity outcome. For example, it is known that calorie reduction or reduction in oxidative stress can lead to increased longevity, but precisely predicting longevity from this information alone is not possible. Given the difficulties of studying aging in humans, the roundworm, Caenorhabditis elegans, will be used as a model to link the activity of specific genes known to affect aging. A mathematical model of the relationship between environment, genes, and longevity will be generated to reveal which genes and environments are most important in determining aging and longevity and to enable the prediction of lifespan. This information will be used in future work that focuses on whether these predictions can be extended to other organisms, and ultimately to humans. Through this work, two graduate students and one postdoctoral researcher will receive interdisciplinary training. In addition, this project will support a Latinx-directed STEM initiative for high-school students.The project's main goal is to develop an experimental and analytical pipeline that will enable the establishment of rules of lifespan determination in the model organism Caenorhabditis elegans. Mathematical and statistical models that can predict lifespan of an individual based on lifelong activity of key aging pathways will be developed. The research tests whether variability in activity of key genes (due to biological noise or environmental or genetic perturbations) is propagated to variability in lifespan. To address this question, a microfluidic platform that enables monitoring of multiple individuals throughout their lifespan, while quantifying the activity of key aging pathways through endogenous fluorescent reporters, will be developed. The proposed platform will allow data pairing, where gene activity at the single individual level can be paired with its lifespan. Experimental tools that enable simultaneous quantitative analysis of in vivo gene activity and combinatorial environmental perturbations will be developed. These tools hinge on microfluidics, computer vision, automation, and new reporter strains engineered by CRISPR to track gene activity under endogenous regulatory control. The acquired data sets will be used to derive data-driven mathematical models that describe the stochastic dynamics of gene activity and its downstream phenotypic outcome: lifespan. Novel statistical techniques will be combined with mathematical models to infer phenotypic heterogeneity and robustness within populations. Interdisciplinary training will be provided to two graduate students and one postdoctoral researcher, and the award will support an educational program directed at broaden participation of Latinx high-school students in science.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.