Vitamin D and Barrier Function

维生素 D 和屏障功能

• 批准号: 7066124
• 负责人: Martin HEWISON
• 金额: $ 27.72万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-26 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7066124
• 关键词: 1,25 dihydroxycholecalciferol; disease /disorder model; disease /disorder proneness /risk; gastrointestinal epithelium; genetically modified animals; hormone regulation /control mechanism; immune response; immunoregulation; inflammation; inflammatory bowel diseases; laboratory mouse; molecular pathology; mucosal immunity; steroid hormone; steroid hormone biosynthesis; vitamin D deficiency; vitamin biosynthesis; vitamin receptor

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.

描述（由申请人提供）：维生素D的合成和反应机制是遗传学上古老的。维生素D由单细胞植物和动物产生。维生素D受体（VDR）蛋白的祖先首先出现在蠕虫中。相比之下，维生素D在钙和骨稳态中的作用在有骨骼的动物中进化得更晚。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]这种功能在更先进的物种中，特别是在今天的人类中仍然起作用吗？假设[1]维生素D系统的中心功能是局部的，而不是血液传播的，在本质上，旨在积极保护上皮屏障（即从宿主中排除入侵者），[2]这种功能不是退化的，在高级脊椎动物中仍然活跃，包括我们自己的物种。在追求的假设“维生素D激素（1，25（OH）2D 3）是一个本地生产和本地活跃的因素，在体内的行为，以修改屏障功能”，这项研究计划将采用最先进的体内和体外分子技术在转基因小鼠模型，解决以下实验问题和相关的假设，具有特别相关的人类健康和疾病。 首先，减少局部生产的1，25（OH）2D 3导致减少上皮屏障保护？据推测，动物携带有针对性的破坏基因编码的酶，使激素将更容易受到肠道入侵的有毒化学品和传染性病原体。其次，考虑到数百万人缺乏足够的维生素D营养，维生素D不足如何影响屏障完整性？理论上，维生素D不足将妨碍体内屏障完整性。第三，如果维生素D激素在活动性炎症部位过量产生，就像克罗恩病患者一样，它过量产生的后果是什么？有人提出，局部过量生产的1，25（OH）2D 3具有双重功能，以平息炎症反应，并保持粘膜的完整性。预计在屏障部位合成的1，25（OH）2D 3将显示出增强屏障保护作用，为潜在病原体入侵部位的1，25（OH）2D 3的肾外合成提供了解释。预计这里计划的实验将：1）揭示维生素D激素在维持哺乳动物宿主与其环境之间的健康分离中的古老作用; 2）提供在感染性或炎症性疾病威胁屏障完整性时如何最好地在人类中使用这些屏障保护作用的见解。