Calcium Control of Enamel Development

牙釉质发育的钙控制

• 批准号: 9493459
• 负责人: Rodrigo S. Lacruz
• 金额: $ 39.63万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-07 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9493459
• 关键词: Address; Adult; Affect; Agonist; Ameloblasts; Amelogenesis Imperfecta; Animals; Biological Process; Birth; Buffers; Calcineurin; Calcium; Caries prevention; Cells; Cellular Stress; Clinical; Data; Defect; Dental Enamel; Development; Down Syndrome; Dyes; Electron Microscopy; Elements; Enamel Formation; Endoplasmic Reticulum; Environment; Frequencies; Fura-2; Gene Expression; Gene-Modified; Genes; Genetic Diseases; Goals; Growth; Hardness Tests; Health; Histologic; Homeostasis; Hour; Human Genetics; ITPR1 gene; Inositol; Knockout Mice; Knowledge; Lead; Link; Measurement; Mediating; Minerals; Monitor; Mus; Mutation; NFAT Pathway; Oral; Organ; Pathway interactions; Patients; Pattern; Physiological; Preventive; Process; Proteins; Reporting; Role; Second Messenger Systems; Skin; Sweat Glands; Testing; Tissues; Tooth Diseases; Tooth structure; Western Blotting; Work; ameloblastin; biophysical techniques; bone; calcification; experimental study; gene function; inhibitor/antagonist; interest; microCT; mineralization; oral bacteria; overexpression; paralogous gene; public health relevance; ratiometric; receptor

 DESCRIPTION (provided by applicant): Calcium (Ca2+) is a key regulator of a broad range of biological functions and is also a key element in the composition of dental enamel. Ca2+ must reach the forming enamel layer but how this process is regulated in ameloblasts is poorly understood. Our goal is to identify key pathways used by ameloblasts to regulate Ca2+ dynamics, in particular the required mechanisms for Ca2+ entry and pathways activated upon increases in cytosolic Ca2+ concentration. Deficiencies in the normal functioning of these pathways result in abnormal enamel that is prone to dental disease which can act as a host environment for oral bacteria. The focus of this proposal is to identify the functions of the store operated Ca2+ release-activated Ca2+ (CRAC) channels in enamel development. CRAC channels comprise important Ca2+ influx mechanisms activated following Ca2+ release from the endoplasmic reticulum (ER). The importance of Ca2+ influx via CRAC channels pathway in ameloblasts is understood by clinical reports describing hypo-calcified amelogenesis imperfecta in patients with mutations to STIM1 and ORAI1. However our understanding of CRAC channels function in enamel is limited as Stim1-/- and Orai1-/- animals die around birth. To address this problem, we developed several conditional knockout mice that specifically analyze the function of CRAC channels with particular reference to dental enamel formation. The ensuing Ca2+ entry via CRAC activates the calcineurin-NFAT pathway, which up-regulates the regulator of calcineurin (RCAN1). Although we find that NFAT and RCAN1 are expressed in enamel cells, and that this pathway is active during enamel development, the functions of these genes in enamel development are unknown. We are particularly interested in RCAN1 as Down syndrome patients present with a host of enamel deficiencies including abnormal mineralization and thinner enamel. Down syndrome is one of the most common human genetic disorders (frequency is 1 in ~700 births) characterized by elevated levels of RCAN1 in several tissues. The cause of growth alterations in the enamel of Down syndrome patients remains unknown. Our proposed studies will increase our understanding of enamel development. Such knowledge will impact caries prevention and has broader implications in bone homeostasis/development and in the development of ectodermal organs as some of these pathways are shared. The proposed work will also lead to a better understanding of systemic effects of CRAC channel function.

 描述（由适用提供）：钙（Ca2+）是广泛的生物学功能的关键调节剂，也是牙釉质组成的关键元素。 Ca2+必​​须达到形成的搪瓷层，但是如何在成成布中调节此过程的理解很少。我们的目标是确定成成木细胞用于调节Ca2+动力学的关键途径，特别是在胞质CA2+浓度增加时激活的Ca2+进入的所需机制和途径。这些途径正常功能的缺陷导致异常牙釉质，容易发生牙齿疾病，可以充当口服细菌的宿主环境。该建议的重点是确定商店的功能 在搪瓷发育中操作的Ca2+释放激活的Ca2+（CRAC）通道。 CRAC通道包含重要的Ca2+影响机制，后Ca2+从内质网（ER）释放后被激活。通过临床报道描述了突变对STIM1和ORAI1的突变患者，通过描述了降解性的ameleogeness Imperfecta的临床报道来理解Ca2+通过CRAC通道途径在成纤维细胞中的重要性。但是，随着imn1-/ - 和orai1 - / - 动物在出生时死亡，我们对牙釉质中CRAC通道功能的理解受到限制。为了解决这个问题，我们开发了几只条件敲除小鼠，这些小鼠专门分析了CRAC通道的功能，特别是指牙釉质形成。确保通过CRAC进入CA2+进入钙调神经素-NFAT途径，该途径上调了钙调蛋白的调节剂（RCAN1）。尽管我们发现NFAT和RCAN1在搪瓷细胞中表达，并且该途径在搪瓷发育过程中是活跃的，但是这些基因在搪瓷发育中的功能尚不清楚。我们对RCAN1特别感兴趣，因为唐氏综合症患者出现了许多搪瓷缺陷，包括异常矿化和较薄的搪瓷。唐氏综合症是最常见的人类遗传疾病之一（频率为1英寸〜700个出生），其特征是多种组织中RCAN1的水平升高。唐氏综合症患者搪瓷生长改变的原因仍然未知。我们提出的研究将增加我们对搪瓷发展的理解。这种知识将影响预防，并在骨体内稳态/发育以及外胚层器官的发展中具有更大的影响，因为这些途径中的某些途径被共享。拟议的工作还将更好地理解CRAC通道功能的全身效应。