RoL:NSF-BSF: (Dia)pausing aging. The role of vitamin D synthesis and signaling in the control of development, aging, and pace of life

所有物种的典型寿命是由遗传和环境因素共同决定的，遗传因素是最重要的。人的一生通常被划分为独立的时期，如胚胎发育、青春期或衰老，尽管这些阶段都是一个连续过程的一部分，很可能是由相同的基因控制和调节的。生命节奏指的是生物体在这些发育阶段的移动速度，新陈代谢率、生命节奏和寿命之间存在着普遍的相关性；高代谢率通常导致更快的生活节奏和更短的寿命。乌龟（慢，低代谢，长寿）和兔子（快，高代谢，短命）的经典故事说明了这种基本关系。已知所有动物都有一组共同的基因参与胚胎发育，决定代谢率，并影响衰老过程。在我们对生活节奏和衰老的认识中，一个重要的空白是这些共享基因被不同地调节以产生“快”或“慢”生活节奏的机制。这项工作利用了一年生鳉的独特生物学特性，研究了在一个物种的不同生命阶段，极端的生活节奏是如何被调节的。这些小鱼在发育过程中进入深度休眠状态，可以让生命“暂停”数月甚至数年。然而，一旦成年，它们衰老得很快，几个月内就会死亡。这项工作的目的是了解维生素D在调节所有动物的发育和衰老速度方面的作用，并以每年捕杀的动物为模型。该项目让学生学习尖端的基因编辑技术，提供科学教育培训，直接向公众提供信息，并支持科学领域的国际合作。本项目利用CRISPR/Cas9技术敲除维生素D3 1-a羟化酶（cyp27b1）酶，探索维生素D3信号通路；这种酶负责产生激活维生素D受体（VDR）的活性维生素。这些转基因动物将使我们能够确定VDR，一种具有广泛作用和多种蛋白质伴侣的核受体，如何在个体的整个生命周期内减轻复杂的表型。这项工作将探索VDR如何通过与各种染色质修饰酶合作来改变基因组的表观遗传景观。重要的是，这项工作有可能改变我们对环境线索如何整合到脊椎动物发育程序中的理解，以确定滞育和衰老等复杂表型。最后，由于这项工作侧重于这一迷人而复杂的生命史的两个独立起源，这项工作将为探索趋同进化的机制和确定核受体（如VDR）的混杂性质如何用于产生复杂的表型提供机会。该基金由生物科学理事会综合有机体系统部的综合生态生理学项目、分子和细胞生物科学部的细胞动力学和功能集群以及新兴前沿部的生命规则共同资助。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。

The typical lifespan of all species is determined by both genetic and environmental factors, with genetic factors being of primary importance. Lifespan is often divided into and studied as discrete periods such as embryonic development, puberty, or senescence, although these phases are all part of a continuous process that is likely controlled and regulated by the same genes. Pace of life refers to the speed with which organisms move through these developmental phases, and there is a general correlation between metabolic rate, pace of life, and lifespan; high metabolic rates typically lead to faster pace of life and shorter lifespans. This basic relationship is illustrated in the classic story of the tortoise (slow, low metabolism, long-lived) and the hare (fast, high metabolism, short-lived). There are a shared group of genes in all animals that are known to participate in embryonic development, determination of metabolic rate, and affect the process of senescence (aging). One important gap in our knowledge of pace of life and aging is the mechanisms by which these shared genes are regulated differently to generate a “fast” or “slow” pace of life. This work capitalizes on the unique biology of annual killifishes to study how extremes in pace of life are regulated during different phases of the lifespan, but within a single species. These small fish can put life “on hold” for months or even years by entering into a profound state of dormancy during development. However, once they become adults, they age very rapidly and die within a few months. The goal of this work is to understand the role of vitamin D in regulating rate of development and aging in all animals using annual killifishes as a model. This project engages students in cutting-edge gene editing techniques, provides training in science education to help directly inform the public, and supports international collaboration in the sciences.This project explores vitamin D3 signaling by using CRISPR/Cas9 technology to knockout the vitamin D3 1-a hydroxylase (cyp27b1) enzyme; the enzyme responsible for production of the active form of the vitamin that activates the vitamin D receptor (VDR). These genetically-modified animals will allow us to determine how the VDR, a nuclear receptor with broad actions and multiple protein partners, can mitigate complex phenotypes across the life span of an individual. This work will explore how the VDR may alter the epigenetic landscape of the genome through partnering with various chromatin modifying enzymes. Importantly, this work has the potential to transform our understanding of how environmental cues may be integrated into vertebrate developmental programs to determine complex phenotypes like diapause and aging. Finally, because the work focuses on two independent origins of this fascinating and complex life history, the work will provide an opportunity to explore mechanisms of convergent evolution and to identify how the promiscuous nature of nuclear receptors such as the VDR can be used to generate complex phenotypes.This grant was cofunded by the Integrative Ecological Physiology Program in the Division of Integrative Organismal Systems, the Cellular Dynamics and Function Cluster in the Division of Molecular and Cellular Biosciences, and The Rules of Life in the Division of Emerging Frontiers in Directorate for Biological 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.