Vitamin D and Barrier Function

描述（由申请人提供）：维生素D的合成和反应机制在系统发育上是古老的。单细胞植物和动物都能产生维生素D。祖先维生素D受体（VDR）蛋白最早出现在蠕虫体内。相比之下，在有骨骼的动物中，维生素D在钙和骨骼稳态中的作用进化得要晚得多。这就引出了两个重要的问题：维生素D是如何在骨骼发育之前为生物体服务的？今天，这种功能在更高级的物种，特别是人类身上是否仍然有效？据推测，维生素D系统的核心功能[1]是局部的，而不是血源性的，在本质上，[1]被设计为活跃的上皮屏障保护（即排除来自宿主的入侵者），[1]的功能不是退化的，在包括我们自己的物种在内的高级脊椎动物中仍然活跃。为了追求“维生素D激素（1,25(OH)2D3）是一种局部产生和局部活跃的因子，可以改变体内的屏障功能”的假设，该研究计划将在转基因小鼠模型中采用最先进的体内和体外分子技术，以解决以下实验问题和与人类健康和疾病特别相关的相关假设。

DESCRIPTION (provided by applicant): The vitamin D synthetic and response mechanisms are phylogenetically ancient. Vitamin D is produced by both single-cell plants and animals. The ancestral vitamin D receptor (VDR) proteins first appeared in worms. By contrast, the role of vitamin D in calcium and bone homeostasis evolved much later in animals with skeletons. This begs two important questions: [1] How did vitamin D serve the organism in advance of skeletal development?; and [2] Is this function still operative in more advanced species, specifically man, today? It is hypothesized that [1] a central function of the vitamin D system is local, not blood-borne, in nature, designed to be active in epithelial barrier protection (i.e. exclusion of invaders from the host) and [2] this function is not vestigial, remaining active in advanced vertebrates, including our own species. In pursuit of the hypothesis 'that the vitamin D hormone (1,25(OH)2D3) is a locally-produced and locally-active factor that acts to modify barrier function in vivo', this research program will employ state-of-the-art in vivo and in vitro molecular technologies in transgenic mouse models that address the following experimental questions and associated hypotheses that have particular relevance to human health and disease. First, does diminished local production of the 1,25(OH)2D3 result in diminished epithelial barrier protection? It is hypothesized that animals harboring targeted disruption of the gene that encodes the enzyme which makes the hormone will be more susceptible to gut invasion by noxious chemicals and infectious agents. Second, considering the millions of humans that suffer from lack of adequate vitamin D nutrition, how does vitamin D insufficiency affect barrier integrity? It is theorized that vitamin D insufficiency will hamper barrier integrity in vivo. And third, if the vitamin D hormone is over-produced at sites of active inflammation, as it is in patients with Crohn's disease, what are the consequences of its over-production? It is proposed that local overproduction of 1,25(OH)2D3 has a dual function to quell inflammatory responses and to preserve mucosal integrity. It is anticipated that 1,25(OH)2D3 synthesized at barrier sites will be shown to amplify barrier protection, providing an explanation for the extra-renal synthesis of the 1,25(OH)2D3 at sites of potential pathogen invasion. It is anticipated that the experiments planned here will: 1] uncover the ancient action of the vitamin D hormone in the preservation of a healthy separation between the mammalian host and its environment; and 2] provide insight in how best to use these barrier preserving actions in humans when infectious or inflammatory disease threatens barrier integrity.