Vitamin D Metabolism and Lifespan Determination

描述(申请人提供)：维生素D在骨矿物质平衡中起关键作用，但也有广泛的其他生理作用。缺乏25-羟基维生素D是主要的循环形式，与年龄相关的慢性疾病的风险增加有关，包括阿尔茨海默病、帕金森氏病、认知障碍和多种癌症。然而，将维生素D缺乏与各种慢性病联系起来的机制尚不清楚，但人们怀疑老年人缺乏维生素D。我们发现，成年秀丽线虫(C.elegans)暴露于D3可以防止在衰老和延长寿命过程中各种不溶蛋白质的积累。它还可以阻止Abeta多肽的聚集。我们有初步数据表明，这些有益的作用需要内质网未折叠蛋白反应(ER UPR)和可能作为维生素D受体的核激素受体(NHR-226)。我们的目标是揭示维生素D的作用机制，以期了解维生素D在人类健康中所起的作用。我们建议确定维生素D的作用是通过核机制还是非核机制，并确定维生素如何影响蛋白质的动态平衡。要做到这一点，我们必须首先了解线虫体内的维生素D代谢，以便我们能够操纵维生素D的作用。我们预计我们的结果可能会影响维生素D与人类慢性病的研究。

DESCRIPTION (provided by applicant): Vitamin D has a critical role in bone mineral homeostasis but also has a broad range of other physiological effects. Deficiency of 25-hydroxyvitamin D, the major circulating form, is associated with increased risk of age-related chronic conditions including Alzheimer's disease, Parkinson's disease, cognitive impairment and a wide range of cancers. However, the mechanism that links vitamin D deficiency to diverse chronic diseases is unknown but it is suspected that elderly populations are vitamin D deficient. We have discovered that exposure of adult Caenorhabditis elegans (C. elegans) to D3 prevented the accumulation of a diverse range of insoluble proteins during aging and extended lifespan. It also prevents the aggregation of Abeta peptide. We have preliminary data that suggests that these beneficial effects require the endoplasmic reticulum unfolded protein response (ER UPR) and a nuclear hormone receptor (NHR-226) which may be acting as a vitamin D receptor. We aim to uncover the mechanism at play with a view to understanding the role played by vitamin D in human health. We propose to establish whether the effects of vitamin D are through a nuclear or a non-nuclear mechanism and establish how vitamin is affecting protein homeostasis. To do so, we must first understand vitamin D metabolism in C. elegans so we can manipulate vitamin D action. We expect our results could be influential how vitamin D is studied in relation to human chronic disease.