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都是由遗传和环境因素决定的，其中遗传因素是首要的。寿命通常被划分为离散的阶段，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。生活节奏是指生物体通过这些发育阶段的速度，代谢率、生活节奏和寿命之间普遍存在相关性；高代谢率通常会导致更快的生活节奏和更短的寿命。这种基本的关系在乌龟(缓慢，低代谢，长寿)和野兔(快，高新陈代谢，短命)的经典故事中得到了说明。在所有动物中都有一组共同的基因，它们参与胚胎发育，决定代谢率，并影响衰老(衰老)过程。在我们对生活节奏和衰老的了解中，一个重要的缺口是这些共享基因被不同地调控以产生“快”或“慢”生活节奏的机制。这项工作利用每年千岁的独特生物学，研究在生命的不同阶段，但在单一物种内，生活节奏的极端是如何受到调节的。这些小鱼可以在发育过程中进入深度休眠状态，从而使生命“搁置”数月甚至数年。然而，一旦他们成年，他们就会非常迅速地衰老，并在几个月内死亡。这项工作的目标是了解维生素D在调节所有动物的发育和衰老速度中的作用，并以每年的千克寿命为模型。该项目让学生学习尖端基因编辑技术，提供科学教育培训，帮助直接向公众提供信息，并支持科学领域的国际合作。该项目通过使用CRISPR/Cas9技术敲除维生素D3 1-a羟基酶(Cyp27b1)，探索维生素D3信号传递；该酶负责产生激活维生素D受体(VDR)的维生素活性形式。这些转基因动物将使我们能够确定VDR是一种核受体，具有广泛的作用和多个蛋白质伙伴，如何在一个人的一生中减轻复杂的表型。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格局。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以确定滞育和衰老等复杂表型的理解。最后，由于这项工作聚焦于这段迷人而复杂的生命史的两个独立起源，这项工作将提供一个机会来探索融合进化的机制，并确定如何利用VDR等核受体的混杂性质来产生复杂的表型。这项拨款是由综合组织系统部门的综合生态生理学计划、分子和细胞生物科学部门的细胞动力学和功能集群以及生物科学理事会新兴前沿部门的生命规则共同资助的。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，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.