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。祖传维生素D受体（VDR）蛋白首先出现在蠕虫中。相比之下，维生素D在钙和骨稳态中的作用在骨骼动物中很久以后演变。这就提出了两个重要的问题：[1]维生素D在骨骼发育之前如何服务？ [2]当今该功能在更高级物种（特别是人类）中是否仍在操作？假设[1]维生素D系统的核心功能是局部的，而不是血传播，本质上是在上皮屏障保护中活跃的（即排除在宿主中的入侵者），[2]此功能不是遗传性的，在包括我们自己的物种在内的先进脊椎动物中保持活性。为了追求假设：“维生素D激素（1,25（OH）2d3）是本地产生的局部活性因素，可用于改变体内的屏障功能”，该研究计划将在体内进行最新的体内和替代性小鼠模型中的体外分子技术，以解决人类疾病的疾病，并与人类疾病相关。首先，减少了1,25（OH）2d3的本地生产会导致上皮屏障保护减少吗？假设具有靶向靶向的基因的动物，该基因编码酶的基因，这使激素更容易受到有害化学物质和感染剂的肠道侵袭的影响。其次，考虑到数以百万计的人缺乏足够的维生素D营养的人，维生素D不足如何影响屏障完整性？从理论上讲，维生素D功能不全会在体内阻碍屏障的完整性。第三，如果维生素D激素在活性炎症部位过量产生，就像在克罗恩病患者中一样，其过量产生的后果是什么？有人提出，1,25（OH）2d3的局部过量生产具有双重功能，可以平息炎症反应并保留粘膜完整性。预计在屏障部位合成的1,25（OH）2d3将显示出扩大屏障保护，从而为潜在病原体入侵的1,25（OH）2D3的肾上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激素在保存哺乳动物宿主与其环境之间健康分离方面的古老作用； [2]提供有关如何最好地在感染或炎症性疾病威胁障碍完整性时如何最好地使用这些障碍行动的见解。

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.