Vitamin D and Barrier Function

描述(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。维生素D是由单细胞植物和动物产生的。祖先的维生素D受体(VDR)蛋白最早出现在蠕虫中。相比之下，在有骨骼的动物中，维生素D在钙和骨骼动态平衡中的作用进化得更晚。这就引出了两个重要的问题：[1]维生素D是如何在骨骼发育之前为机体服务的？[2]这种功能在更高级的物种，特别是今天的人类中是否仍然起作用？假设[1]维生素D系统的一个中心功能是局部的，而不是通过血液传播的，在自然界中被设计为活跃于上皮屏障保护(即从宿主中排除入侵者)和[2]该功能不是退化的，在包括我们自己的物种在内的高级脊椎动物中仍然活跃。为了实现这样的假设，即维生素D激素(1，25(OH)2D3)是一种本地生产的局部活性因子，可在体内改变屏障功能，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，以解决以下与人类健康和疾病特别相关的实验问题和相关假设。 首先，局部产生的1，25(OH)2D3的减少是否会导致上皮屏障保护的减弱？据推测，编码荷尔蒙的酶的基因被有针对性地破坏的动物将更容易受到有毒化学物质和感染性物质的肠道入侵。其次，考虑到数百万人缺乏足够的维生素D营养，维生素D不足如何影响屏障的完整性？理论上，维生素D缺乏会阻碍体内屏障的完整性。第三，如果维生素D激素在炎症活跃的部位过度产生，就像克罗恩病患者那样，其过度产生的后果是什么？有人认为局部过量的1，25(OH)2D3具有平息炎症反应和保护粘膜完整性的双重功能。预计在屏障部位合成的1，25(OH)2D3将被证明能放大屏障保护，为在潜在病原体入侵部位肾外合成1，25(OH)2D3提供了解释。预计这里计划的实验将：1)揭示维生素D激素在保持哺乳动物宿主与其环境之间的健康分离方面的古老作用；2)提供关于当传染病或炎症性疾病威胁屏障完整性时如何最好地在人类身上使用这些屏障保护作用的见解。

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.