Molecular mechanisms of oral deficiencies in Down syndrome

唐氏综合症口腔缺陷的分子机制

• 批准号: 10658410
• 负责人: Rodrigo S. Lacruz
• 金额: $ 151.33万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658410
• 关键词: Address; Ameloblasts; Amylases; Area; Biogenesis; Calcineurin; Calcineurin inhibitor; Calcium Signaling; Carbachol; Cell Line; Cells; Chromosome 21; Confocal Microscopy; Crystal Formation; Data; Defect; Dental; Dental Enamel; Development; Down Syndrome; Elements; Enamel Formation; Enzyme-Linked Immunosorbent Assay; Enzymes; Feedback; Fluids and Secretions; Foundations; Gene Dosage; General Population; Generations; Genes; Gland; Glycolysis; Goals; Growth; Health; Heterozygote; Histology; Human Chromosomes; Image; Individual; Infection; Knockout Mice; Knowledge; Label; Longevity; Maturation-Stage Ameloblast; Measures; Mechanics; Mediating; Membrane Potentials; Mitochondria; Mitochondrial Matrix; Modeling; Molecular; Morphology; Mus; NADH; Oral; Oral cavity; Oral health; Osmosis; Oxygen Consumption; PPP3CA gene; Parotid Gland; Pathology; Patients; Phase; Pilocarpine; Predisposition; Process; Production; Property; Protein Secretion; Protein phosphatase; Proteins; Publishing; Quality of life; Quantitative Reverse Transcriptase PCR; Reporter; Reporting; Research; Research Personnel; Role; Saliva; Salivary Glands; Secondary to; Secretory Vesicles; Signal Transduction; Sorting; Speech; Taste Perception; Testing; Thinness; Time; Tooth structure; Trisomy; United States National Institutes of Health; Vesicle; Xerostomia; antimicrobial; calcification; deciduous tooth; dosage; experimental study; induced pluripotent stem cell; mechanical properties; mineralization; mitochondrial dysfunction; mitochondrial membrane; mouse model; nanoindentation; overexpression; permanent tooth; prevent; response; saliva secretion; skeletal; solute; trafficking; transcriptome sequencing; transcriptomic profiling; uptake; water channel

Project Summary/Abstract: Individuals with Down syndrome (DS) contend with a diversity of oral anomalies including poor saliva production and enamel defects that manifest as hypoplasia (thinner enamel) and hypomineralization. The molecular mechanisms responsible for these alterations are not known. DS enamel defects are developmental and not simply secondary to hyposalivation. Saliva is essential to overall oral health, keeping the oral cavity moist and providing important support for speech and taste. It also contains solutes and enzymes that help prevent bacterial attack. Tooth enamel and saliva together provide a barrier against bacterial attack and can have a significant impact on health and quality of life. Regulator of calcineurin 1 (RCAN1) is a gene on human chromosome 21 (Hsa21), trisomy of which causes DS. RCAN1 is a feed-back inhibitor of calcineurin (Cn) a Ca2+-activated protein phosphatase that is central to a diversity of intracellular signaling cascades. Loss of Cn function has been shown to alter the water channel aquaporin, and in salivary glands, disrupts vesicle trafficking essential for saliva protein secretion. The goal of this proposal is to understand how salivary gland and enamel formation are altered in DS on a molecular level and to define the role of RCAN1/Cn in this process. In strong support, our preliminary data show that Dp16 mice [Dp(16)1Yey] an established mouse model of DS, have mechanically weak and morphologically abnormal enamel. We show that RCAN1 expression is upregulated in the mineralization phase and that overexpressing RCAN1 in an ameloblast cell line significantly alters mitochondrial function and increases ROS generation. Our co-investigator has demonstrated that changes in RCAN1 gene dosage are sufficient to alter mitochondrial dynamics and function in induced pluripotent stem cells (iPSCs) derived from individuals with DS. There are two central testable hypotheses in the proposed studies: 1) RCAN1 disrupts enamel crystal formation in DS by altering mitochondrial function in ameloblasts and 2) RCAN1 suppression of Cn signaling in DS disrupts Ca2+ signaling in salivary glands leading to hyposalivation. We will use DS mouse models (Dp16 mice, Rcan1-KO mice, Dp16 x Rcan1-KO mice) to address the role of mitochondria in the ameloblasts of these mice and will use mice expressing fluorescently labelled secretory and maturation stage. To address the role of RCAN1 trisomy in salivary glands (SG), we will use the Dp16 mice and will cross them with GFP mice highlighting secretory vesicles in SG to analyze calcium signaling, salivation as well as protein and solute content in saliva. The proposed studies are significant because they will both advance our understanding of the mechanisms through which perturbation of normal mitochondrial function, such as occurs in DS, can impact dental health ameloblast mitochondria and will elucidate the mechanisms contributing to hyposalivation in DS.

项目摘要/摘要：唐氏综合症（DS）患者面临着多种口头表达方式的挑战