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由遗传和环境因素决定，其中遗传因素最为重要。寿命通常被划分为离散的时期，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，可能由相同的基因控制和调节。生活节奏是指生物体在这些发育阶段的速度，代谢率、生活节奏和寿命之间存在一般相关性;高代谢率通常会导致生活节奏加快和寿命缩短。这种基本关系在经典的乌龟（慢，低代谢，长寿）和兔子（快，高代谢，短命）的故事中得到了说明。所有动物都有一组共同的基因，已知它们参与胚胎发育，决定代谢率，并影响衰老（老化）过程。我们对生活节奏和衰老的认识中的一个重要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鱼独特的生物学特性，研究了在生命的不同阶段，但在一个物种内，生活节奏的极端是如何调节的。这些小鱼在发育过程中进入深度休眠状态，可以使生命“暂停”数月甚至数年。然而，一旦他们成为成年人，他们的年龄非常迅速，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，使用一年生的鳉鱼作为模型。该项目让学生参与尖端的基因编辑技术，提供科学教育培训以帮助直接告知公众，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羟化酶（cyp 27 b1）来探索维生素D3信号传导;负责生产激活维生素D受体（VDR）的维生素活性形式的酶。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以确定滞育和衰老等复杂表型的理解。最后，由于这项工作的重点是这一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，探索趋同进化的机制，并确定如何利用核受体（如VDR）的混杂性质来产生复杂的表型。该奖项反映了NSF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.