Deterministic and stochastic effects of diet on demography Administrative Supplement to AG049396

描述(由申请人提供)：饮食在许多健康结果中起着关键作用，从疾病发生率到生活质量到长寿本身。已知的大多数受饮食和营养影响的生物系统都参与调节生长、发育、繁殖和对压力的反应之间的平衡。众所周知，饮食治疗，如卡路里限制，以及某些突变，如涉及胰岛素信号通路的突变，可以延长寿命，但往往会对生殖产生负面影响。然而，这些干预措施的确切人口后果在很大程度上是未知的。任何给定的个体将如何对特定的饮食制度做出反应，取决于遗传、随机环境差异和饮食本身的系统效应的复杂组合，从而导致每个个体复杂的随机生命轨迹。了解 这种复杂性的功能基础需要估计许多基因相同的个人的人口轨迹，以便能够描述个人结果的整个分布，还需要一个统计框架，允许将个人差异的累积归因于该个人的固有属性--随机核。模式线虫秀丽线虫特别适合于解决这些问题，因为它已经成为了解应激反应和衰老的遗传和生理基础的核心参与者，并且因为它可以用于产生大量遗传相同的个体进行人口统计分析。在这里，我们建议：(1)利用创新的微流体和统计学方法来精确描述不同饮食输入下的个体人口轨迹；(2)研究发育状态以及胰岛素信号和应激反应通路在面对饮食波动时调节生殖模式变化的作用；以及(3)表征感知在饮食调节生殖模式中的作用。我们将使用定制设计的微流体系统，这些系统(1)提供数万个个体繁殖动态的自动表征，(2)允许精确控制饮食和食物水平，(3)能够基于生理状态(如基因表达水平)对个体进行分类。将使用一个基于随机人口学的新框架来分析数据，以估计在饮食限制和暴露于自然产生的线虫相关细菌的条件下饲养的自然分离物和长寿相关突变体的个体随机核。感知缺陷突变体将被用来区分由感觉输入驱动的生殖调节和代谢状态。综上所述，这项工作将为研究这一重要模型系统内的随机人口学提供新颖和全面的方法，并将提供关于导致延长寿命的治疗的影响如何在个体的生殖寿命中传播的见解。

DESCRIPTION (provided by applicant): Diet plays a critical role in many health outcomes, from incidence of disease to quality of life to longevity itself. Most of the biological systems known to be influenced by diet and nutrition are involved in mediating the balance between growth, development, reproduction, and the response to stress. Dietary treatments, such as caloric restriction, and certain mutations, such as those involved in the insulin signaling pathway, are known to increase lifespan yet frequently yield negative effects on reproduction. The precise demographic consequences of these interventions are largely unknown, however. How any given individual will respond to a particular dietary regime depends on a complex combination of genetics, random environmental differences, and the systematic effects of the diet itself, leading to complex stochastic life trajectories for each individual. Understanding the functional basis of this complexity requires estimates of the demographic trajectories of numerous genetically identical individuals so that the entire distribution individual outcomes can be characterized and also requires a statistical framework that allows for the accumulation of individual differences to be attributed to the inherent properties-the stochastic kernel-of that individual. The model nematode Caenorhabditis elegans is especially amenable to addressing these problems because it has become a central player in understanding the genetic and physiological bases of stress response and aging and because it can be used to generated large numbers of genetically identical individuals for demographic analysis. Here, we propose: (1) to utilize innovative microfluidic and statistical approaches to precisely characterize individual demographic trajectories under different dietary inputs, (2) to examine the role of developmental state and insulin signaling and stress response pathways in mediating variation in reproductive patterns in the face of dietary fluctuations, and (3) to characterize the role of perception in dietary modulation of reproductive patterning. We will use custom designed microfluidic systems that (1) provide automated characterization of the reproductive dynamics of tens of thousands of individuals, (2) allow precise control of diet and food level, and (3) enable sorting of individuals based on physiological state, such levels of gene expression. A novel framework based on stochastic demography will be used to analyze the data in order to estimate individual stochastic kernels for natural isolates and longevity-related mutants reared under conditions of dietary restriction and exposure to naturally occurring nematode-associated bacteria. Perception deficient mutants will be used to distinguish modulation of reproduction driven by sensory input versus metabolic state. Taken together, this work will provide novel and comprehensive approaches for studying stochastic demography within this important model system and will provide insights into how the impact of treatments leading to increased longevity propagate throughout the reproductive lifespan of an individual.