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.

描述（由申请人提供）：钙是多种生物功能的关键调节剂，也是牙釉质成分的关键元素。在釉质形成的成熟阶段，随着釉质晶体宽度和厚度的扩大，Ca2+的需求量增加。钙必须到达形成的牙釉质层，但对于成釉细胞如何调节这一过程却知之甚少。当前牙釉质中 Ca2+ 转运的模型侧重于 Ca2+ 通过进入、转运和挤出步骤的跨细胞通道。尽管一些工作已经报道了转运和挤出步骤，但关于 Ca2+ 进入成釉细胞的机制只有有限的信息。在此拨款提案中，我通过检查商店操作的 Ca2+ 释放激活的 Ca2+ (CRAC) 通道的作用来重点关注进入步骤。 CRAC 通道构成上皮细胞中重要的 Ca2+ 内流机制。 CRAC 通道（STIM1、ORAI1）突变的患者除了免疫系统缺陷外，还存在低钙化釉质生成不全。我的目标是确定 Stim1 和 Orai1 如何参与 Ca2+ 进入以及如何调节该过程。 PI 最近的工作表明，Stim1、Orai1 以及 Ca2+ 信号胆囊收缩素 (Cck) 和 Cck 抑制剂 Rcan1 被确定在成熟过程中显着上调。我已经通过 qPCR、Western blot 和 IHC 证实了这些结果。因此，Ca2+ 通过 CRAC 通道流入成釉细胞以及如何调节该过程对于健康牙釉质的发育非常重要。拟议拨款申请提供的证据将有助于更好地了解 CRAC 功能废除的系统性影响。这也将有助于医生就 CRAC 通道突变患者的牙医就诊做出决定，以预防牙齿问题 公众健康相关性：钙对于牙釉质的正常生物矿化至关重要。成釉细胞对钙的吸收中断会导致成釉细胞不全。我的目标是分析钙储存通道在牙釉质发育中的功能。