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.
