CALCIUM REGULATION IN ORAL HEALTH

口腔健康中的钙调节

• 批准号: 8354594
• 负责人: Rodrigo S. Lacruz
• 金额: $ 10.69万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-13 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8354594
• 关键词: Adult; Affect; Ameloblasts; Amelogenesis; Amelogenesis Imperfecta; Animals; Applications Grants; Biological Process; Calcium; Cells; Cholecystokinin; Collaborations; Cultured Cells; Data; Decision Making; Defect; Dental; Dental Enamel; Dental caries; Dentists; Development; Diagnosis; Dissection; Dyes; Enamel Organ; Epithelial Cells; Family; Genes; Goals; Immune system; Immunofluorescence Immunologic; In Vitro; Incisor; Indium; Intake; Knockout Mice; Link; Mediating; Medical; Metabolism; Michigan; Modeling; Mus; Mutate; Mutation; Oral health; Paraffin Embedding; Pathway interactions; Patients; Phase; Phenotype; Prevention strategy; Process; Protein Isoforms; Rattus; Regulation; Regulatory Pathway; Reporting; Reverse Transcriptase Polymerase Chain Reaction; Role; Route; STIM1 gene; Signal Transduction; Staging; Subfamily lentivirinae; Testing; Thick; Time; Tissues; Toxic effect; Up-Regulation; Visit; Western Blotting; Width; Work; biomineralization; cellular transduction; design; extracellular; genome-wide analysis; inhibitor/antagonist; mineralization; novel; postnatal; prevent; uptake

DESCRIPTION (provided by applicant): Calcium is a key regulator of a broad range of biological functions and is also a key element in the composition of dental enamel. During the maturation stage of amelogenesis, Ca2+ requirements increase as enamel crystals expand in width and thickness. Calcium must reach the forming enamel layer but how this process is regulated in ameloblasts is poorly understood. The current model for Ca2+ transport in enamel focuses on the transcellular passage of Ca2+ via the entry, transit and extrusion steps. Whereas several works have reported on the transit and extrusion steps, only limited information is available for Ca2+ entry mechanisms into ameloblasts. In this grant proposal, I focus on the entry step by examining the role of the store-operated Ca2+ release-activated Ca2+ (CRAC) channels. CRAC channels comprise important Ca2+ influx mechanism in epithelial cells. Patients with mutations to CRAC channels (STIM1, ORAI1) present, in addition to immune system deficiencies, with hypocalcified amelogenesis imperfecta. My goal is to identify how Stim1 and Orai1 are involved in Ca2+ entry and how this process is regulated. Recent work by the PI indicates that Stim1, Orai1 as well as well as the Ca2+ signaling cholecystokinin (Cck) and the Cck inhibitor Rcan1 were identified as being significantly up-regulated in maturation. I have confirmed these results by qPCR, Western blot and IHC. Thus Ca2+ influx into ameloblasts via CRAC channels and how this process is regulated is important for the development of healthy enamel. Evidence contributed by the proposed grant application will help to better understand the systemic effects of CRAC function abrogation. This will also help medical practitioners in making decisions concerning dentist visits to patients with mutations to CRAC channels in order to prevent dental problems PUBLIC HEALTH RELEVANCE: Calcium is critical for the normal biomineralization of enamel. Disruptions to calcium uptake by ameloblasts results in amelogenesis imperfecta. My goal is to analyze the function of calcium-store operated channels in enamel development.

说明(申请人提供)：钙是一系列生物功能的关键调节剂，也是牙釉质成分中的关键元素。在釉质形成的成熟阶段，随着釉质晶体的宽度和厚度的增加，对钙的需求也会增加。钙必须到达形成牙釉质的层，但这一过程在成釉细胞中是如何调节的，人们知之甚少。目前牙釉质中钙离子转运的模型主要集中在钙离子进入、转运和排出过程中的跨细胞转运。虽然已经有几项工作报道了转运和排出的步骤，但只有有限的信息可用于钙离子进入成釉细胞的机制。在这项拨款提案中，我通过研究存储操作的钙释放激活的钙通道(CRAC)的作用，将重点放在进入步骤上。CRAC通道是上皮细胞内钙内流的重要机制。CRAC通道(STIM1，ORAI1)突变的患者除了免疫系统缺陷外，还存在低钙化的釉质形成不全。我的目标是确定STIM1和Orai1是如何参与钙离子内流的，以及这个过程是如何调控的。PI最近的工作表明，STIM1、Orai1以及钙信号通路CCK和CCK抑制剂RCAN1在成熟过程中显著上调。我用定量聚合酶链式反应、免疫印迹和免疫组织化学方法证实了这些结果。因此，钙离子通过CRAC通道进入成釉细胞，如何调控这一过程对健康釉质的发育至关重要。拟议拨款申请提供的证据将有助于更好地理解取消CRAC职能的系统性影响。这也将帮助医生作出决定，牙医访问CRAC频道的突变患者的牙医，以防止牙齿问题 与公众健康相关：钙对牙釉质的正常生物矿化至关重要。成釉细胞对钙的摄取中断会导致成釉细胞发育不全。我的目标是分析钙库操作通道在釉质发育中的作用。