Vitamin D and Barrier Function

维生素 D 和屏障功能

基本信息

批准号：
7422402
负责人：
Martin HEWISON
金额：
$ 26.04万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-26 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7422402
关键词：
25-hydroxyvitamin D Ablation Active Sites Address Affect Animals Arts Biological Preservation Blood Calcitriol Calcium Cell Wall Cells Chemicals Cholecalciferol Crohn&apos s disease Dendritic Cells Development Disease Disruption Endocrine Enlargement of lymph nodes Environment Enzymes Epithelial Epithelium Exclusion Exhibits Genes Granuloma Health Homeostasis Hormones Human In Vitro Infectious Agent Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Intestines Kidney Knockout Mice Laboratories Lipopolysaccharides Lymphatic Diseases Mixed Function Oxygenases Molecular Movement Mus Nature Nematoda Organism Patients Placenta Plants Predisposition Production RNA Interference Research Role Sarcoidosis Severity of illness Site Skeletal Development Skeletal system Skeleton Skin System Technology Testing Tissues Today Transgenic Organisms Tubular formation Vertebrates Vitamin D Vitamin D Deficiency Vitamin D Nutrition Vitamin D3 Receptor Wild Type Mouse autocrine bone design gastrointestinal human disease in vivo insight intestinal epithelium knockout gene macrophage man mouse model paracrine pathogen programs receptor receptor expression research study response

项目摘要

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 的合成和反应机制在系统发育上是古老的。维生素 D 由单细胞植物和动物产生。祖先维生素 D 受体 (VDR) 蛋白首先出现在蠕虫中。相比之下，维生素 D 在钙和骨骼稳态中的作用在有骨骼的动物中进化得要晚得多。这就引出了两个重要问题：[1] 维生素 D 如何在骨骼发育之前为机体提供服务？ [2] 如今，这种功能在更先进的物种（特别是人类）中仍然有效吗？据推测，[1] 维生素 D 系统的核心功能本质上是局部的，而不是血液传播的，旨在积极参与上皮屏障保护（即排除宿主体内的入侵者），并且 [2] 该功能是不是退化的，在高级脊椎动物中仍然活跃，包括我们自己的物种。为了追求“维生素 D 激素 (1,25(OH)2D3) 是一种本地产生的本地活性因子，可以改变体内屏障功能”这一假设，该研究计划将采用最新技术-转基因小鼠模型中的体内和体外分子技术，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，1,25(OH)2D3 的局部产生减少是否会导致上皮屏障保护减弱？据推测，编码产生激素的酶的基因受到有针对性的破坏的动物将更容易受到有毒化学物质和传染源的肠道入侵。其次，考虑到数百万人缺乏足够的维生素 D 营养，维生素 D 不足如何影响屏障完整性？理论上维生素 D 不足会妨碍体内屏障的完整性。第三，如果维生素 D 激素在活动性炎症部位过度产生，就像克罗恩病患者那样，那么过度产生会产生什么后果？有人提出，局部过量产生 1,25(OH)2D3 具有抑制炎症反应和保持粘膜完整性的双重功能。预计在屏障位点合成的 1,25(OH)2D3 将被证明可以增强屏障保护，从而为潜在病原体入侵位点的 1,25(OH)2D3 肾外合成提供解释。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隔离方面的古老作用； 2] 提供了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体中使用这些屏障保护作用的见解。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Vitamin D induces innate antibacterial responses in human trophoblasts via an intracrine pathway.

DOI：
10.1095/biolreprod.108.073577
发表时间：
2009-03
期刊：
Biology of reproduction
影响因子：
3.6
作者：
Liu N;Kaplan AT;Low J;Nguyen L;Liu GY;Equils O;Hewison M
通讯作者：
Hewison M

Reduction of the vitamin D hormonal system in kidney disease is associated with increased renal inflammation.

DOI：
10.1038/ki.2008.453
发表时间：
2008-11
期刊：
KIDNEY INTERNATIONAL
影响因子：
19.6
作者：
Zehnder, Daniel;Quinkler, Marcus;Eardley, Kevin S.;Bland, Rosemary;Lepenies, Julia;Hughes, Susan V.;Raymond, Neil T.;Howie, Alexander J.;Cockwell, Paul;Stewart, Paul M.;Hewison, Martin
通讯作者：
Hewison, Martin

Different dietary combinations of high/low starch and fat with or without bile acid supplementation on growth, liver histopathology, gene expression and fatty acid composition of largemouth bass, Micropterus salmoides.

DOI：
10.1016/j.cbpa.2022.111157
发表时间：
2022-01
期刊：
Comparative biochemistry and physiology. Part A, Molecular & integrative physiology
影响因子：
0
作者：
N. Romano;H. Fischer;Marina M Rubio-Benito;Ken Overtuf;A. Sinha;Prof Vikas Kumar
通讯作者：
N. Romano;H. Fischer;Marina M Rubio-Benito;Ken Overtuf;A. Sinha;Prof Vikas Kumar

Vitamin D metabolism and innate immunity.