Genetic Determinants of Physiological Responses to Fluoride in Bone

骨中氟化物生理反应的遗传决定因素

• 批准号: 8279114
• 负责人: ERIC T. EVERETT
• 金额: $ 49.05万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-05 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8279114
• 关键词: Adverse effects; Affect; Age; Animal Model; Animals; Biological Assay; Biological Markers; Biological Models; Bone Density; Bone Matrix; Candidate Disease Gene; Chemicals; Collection; Computer Simulation; DNA Resequencing; Data; Detection; Dose; Engineering; Fluorides; Food; Future; Gender; Generations; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genetic Variation; Genome; Genome Mappings; Genome Scan; Genotype; Goals; Haplotypes; Hematopoietic; Heritability; Homeostasis; Housing; Human; Inbred C3H Mice; Inbred Mouse; Inbred Strains Mice; Individual; Joints; Knowledge; Laboratories; Ligaments; Literature; Maps; Methods; Molecular; Mus; Osteoblasts; Osteoclasts; Osteogenesis; Osteomalacia; Osteoporosis; Osteosclerosis; Pathway interactions; Phenotype; Physiological; Plasma; Populations at Risk; Postmenopausal Osteoporosis; Property; Proteins; Public Health; Publications; Quantitative Trait Loci; Sample Size; Serum; Site; Testing; Treatment Protocols; Variant; autosome; base; biomineralization; bone; bone cell; bone quality; bone strength; calcification; density; drinking water; exposed human population; fluorosis; genetic analysis; mouse model; novel; osteoclastogenesis; osteoprogenitor cell; progenitor; response; skeletal; soft tissue

DESCRIPTION (provided by applicant): Fluoride in various chemical forms and exposures has been repeatedly shown to have actions on bone matrix and on bone cells (osteoblasts and osteoclasts). The anabolic properties of fluoride were once explored for use in the treatment of postmenopausal osteoporosis. Excessive systemic fluoride can result in calcification of soft tissues (e.g. ligaments), osteosclerosis, osteoporosis, and osteomalacia which can compromise bone quality and strength leading to skeletal fluorosis. Despite a wealth of scientific literature a gap of knowledge exists in understanding the molecular mechanisms of fluoride actions on bone cells. We posit that genetic determinants that encode proteins and pathways involved in bone homeostasis underlie fluoride actions on bone cells and their hematopoietic precursors. Using extended phenotyping, we identified differences in osteoclastogenesis between inbred mouse strains, thus supporting the contribution of genetic background. The goal of the proposed studies, to identify fluoride responsive genetic loci in an animal model using a whole genome approach, will be pursued in the following Specific Aims: SpA1: Quantitative trait loci (QTL) mapping will be performed using C57BL/6J and C3H/HeJ inbred mice as progenitor strains in a two generation cross to produce a panel of F2 progeny. F2 mice will be treated with or without fluoride in their drinking water. Multiparameter phenotyping will be performed: serum biomarkers of bone formation/resorption; ex vivo osteoclastogenesis and osteoprogenitor assays; and ex vivo hematopoietic (CFC) assays will be performed. Additionally, selected bones will be phenotyped for BMD (microCT). A genome scan with an average SNP density of 3 Mb across the autosomes and 7 Mb across Chr. X will be performed followed by genetic analyses using a variety of interval mapping methods. SpA2: First determine fluoride response variation among a collection of domestic and wild type inbred mouse strains utilizing the phenotyping and fluoride treatment protocol above. Second, perform in silico mapping strategies. The broad and long term objectives are to identify and characterize fluoride responsive genetic variations, e.g. polymorphisms, in an animal model and later in humans. Public Health Significance: The goal of this project is to identify fluoride responsive chromosomal regions in an animal model. The long term goals are to characterize fluoride responsive genetic variations in an animal model, to identify those at risk populations who are susceptible to the unwanted or potentially adverse effects of fluoride action, and to elucidate fundamental mechanisms by which fluoride affects biomineralization. This animal studies project will generate interpretable and useful information relevant to public health issues like osteoporosis and skeletal fluorosis.

描述（由申请人提供）：以各种化学形式和暴露的氟化物反复证明对骨基质和骨细胞有作用（成骨细胞和破骨细胞）。曾经探索氟化物的合成代谢特性，用于治疗绝经后骨质疏松症。过度的全身氟化物会导致软组织（例如韧带），骨硬化，骨质疏松症和骨乳核酸的钙化，从而损害骨质和强度，从而导致骨骼荧光症。尽管有很多科学文献，但在理解氟化物对骨细胞的分子机制方面仍然存在差距。我们认为，编码参与骨稳态的蛋白质和途径的遗传决定因素是氟化物对骨细胞及其造血前体的作用。使用扩展的表型，我们确定了近交小鼠菌株之间破骨细胞生成的差异，从而支持遗传背景的贡献。在以下特定目的中，将追求拟议的研究的目的，以鉴定动物模型中的氟化物反应性遗传基因座：SPA1：定量性状基因座（QTL）映射将使用C57BL/6J和C3H/HEJ/HEJ INBRED小鼠作为祖先菌株在两代生产的十字架中以F2 pate r2 for 22进行，将使用C57BL/6J和C57BL/6J和C3H/HEJ IN杂交小鼠进行。 F2小鼠将在饮用水中接受或不带有氟化物的治疗。将进行多参数表分型：骨形成/吸收的血清生物标志物；离体破骨细胞生成和破骨剂分析；将进行体内造血（CFC）测定法。另外，将对BMD（MicroCT）进行选定的骨骼。在常染色体上平均SNP密度为3 MB的基因组扫描，跨CHR的平均SNP密度为7 MB。 X将使用各种间隔映射方法进行遗传分析。 SPA2：首先确定使用表型和氟化物治疗方案的家庭和野生型近交小鼠菌株集合中的氟化物反应变化。其次，以硅映射策略执行。广泛的长期目标是识别和表征氟化物反应良好的遗传变异，例如多态性，在动物模型中，后来在人类中。公共卫生意义：该项目的目的是识别动物模型中氟化物反应式染色体区域。长期目标是表征动物模型中的氟化物反应性遗传变异，以确定那些容易受到氟化物作用的不良或潜在不利影响的风险种群，并阐明氟化物影响生物矿化的基本机制。该动物研究项目将产生与骨质疏松和骨骼氟中毒的公共卫生问题有关的可解释和有用的信息。

项目成果

Renal proteome in mice with different susceptibilities to fluorosis.

• DOI: 10.1371/journal.pone.0053261
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Carvalho JG;Leite Ade L;Peres-Buzalaf C;Salvato F;Labate CA;Everett ET;Whitford GM;Buzalaf MA
• 通讯作者: Buzalaf MA

Bone response to fluoride exposure is influenced by genetics.

• DOI: 10.1371/journal.pone.0114343
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Kobayashi CA;Leite AL;Peres-Buzalaf C;Carvalho JG;Whitford GM;Everett ET;Siqueira WL;Buzalaf MA
• 通讯作者: Buzalaf MA

Fluoride Modulates Parathyroid Hormone Secretion in vivo and in vitro.

• DOI: 10.1159/000438699
• 发表时间: 2015
• 期刊: Cells, tissues, organs
• 作者: Puranik CP;Ryan KA;Yin Z;Martinez-Mier EA;Preisser JS;Everett ET
• 通讯作者: Everett ET