Ion channel mediated control of mophogen signaling for craniofacial development in mammals

离子通道介导的哺乳动物颅面发育的形态原信号传导控制

• 批准号: 10832172
• 负责人: Emily Bates
• 金额: $ 6.31万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-08 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10832172
• 关键词: Affect; Alcohols; Antiepileptic Agents; Binding; Bone Development; Bone Morphogenetic Proteins; Bone Regeneration; Bone Transplantation; Branchial arch structure; Calcium; Cartilage; Cell Communication; Cell Culture Techniques; Cell Differentiation process; Cells; Cephalic; Cleft Palate; Communication; Complex; Craniofacial Abnormalities; Data; Defect; Dental; Development; Developmental Biology; Drosophila genus; Electron Microscopy; Environmental Risk Factor; Face; Foundations; Future; Genetic; Genetic Epistasis; Genetic Transcription; Goals; Growth; Growth Factor; Human; Ion Channel; Ions; Knowledge; Laboratories; Language; Mammals; Mediating; Membrane Potentials; Mesenchymal; Micrognathism; Molecular; Morphogenesis; Mus; Mutant Strains Mice; Mutation; Natural regeneration; Neural Crest; Neural Crest Cell; Neural tube; Neurons; Neurotransmitters; Nose; Palate; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Physiologic pulse; Play; Potassium Channel; Process; Production; Protein Secretion; Regulation; Role; Shapes; Signal Transduction; Signaling Protein; Stimulus; Structure; Structure of beta Cell of islet; Teratogens; Testing; Time; Tooth structure; Trauma; Vesicle; Wing; Work; bioelectricity; bone; bone loss; bone repair; bone visualization; cell motility; cell type; craniofacial; craniofacial bone; craniofacial development; craniofacial disorder; experimental study; fly; genetic analysis; glucose metabolism; insight; insulin secretion; mutant; neural; notch protein; novel; novel strategies; novel therapeutic intervention; pharmacologic; procollagen C-endopeptidase; protein function; reconstruction; response; scaffold; skeletal; small molecule; somitogenesis; stem cells; success; tissue regeneration; tool; tumor; vesicular release

PROJECT SUMMARY Craniofacial reconstruction is required after trauma, tumors, and for craniofacial disorders. Bone grafts and synthetic scaffolds have resulted in limited success. Bone morphogenetic proteins (BMPs) stimulate the production of bone and cartilage, and are necessary for tooth development, palate closure and normal craniofacial development. BMPs are also required for bone repair and can stimulate stem cells to take on cartilage and bone fate. We recently discovered that ion channels control the secretion of BMP in the fruit fly. Our hypothesis is that ion channel activity regulates BMP secretion in mammals in a conserved mechanism. In support of this hypothesis, mice with disrupted potassium channel function have decreased activation of BMP signaling and similar phenotypes to BMP mutants. If our hypothesis proves correct, electrical stimuli or small molecules that affect ion channel activity may provide the ability to control release of BMP for proper bone and tooth development and regeneration. Our long-term goal is to use a novel approach of manipulating cells to secrete endogenous BMP to encourage craniofacial bone development. The first step towards this goal is to determine the mechanism by which an ion channel contributes to BMP signaling in mammals. In this proposal, we use the Kir2.1 potassium (K+) channel to determine the molecular connection between ion conductivity and BMP signaling in mammals. Humans and mice with mutations in Kir2.1 have congenital craniofacial defects including cleft palate, dental defects, and micrognathia showing that this channel plays an essential role in craniofacial development. Aim 1 determines where Kir2.1 acts in the BMP pathway in mammals using epistasis and rescue experiments. Aim 2 tests the hypothesis that ion channels regulate BMP secretion in mammals as they do in flies. In other cell types, ion channels influence intracellular calcium to regulate secretion. In Aim 3, we determine how intracellular calcium influences BMP release. The proposed experiments will lay a foundation for future studies to harness the potential of ion channels to stimulate tissue growth and regeneration.

项目摘要 颅面重建是需要在创伤，肿瘤，颅面疾病。骨移植和 合成支架的成功有限。骨形态发生蛋白（BMP）刺激 骨和软骨的产生，是牙齿发育，腭闭合和正常 颅面发育骨形成蛋白也是骨修复所必需的，可以刺激干细胞承担 软骨和骨的命运。我们最近发现离子通道控制果蝇BMP的分泌。 我们的假设是，离子通道活性调节BMP分泌在哺乳动物中的保守的 机制为了支持这一假设，钾通道功能受损的小鼠 BMP信号传导的激活和与BMP突变体相似的表型。如果我们的假设被证明是正确的， 影响离子通道活性的刺激物或小分子可以提供控制BMP释放的能力， 骨骼和牙齿的正常发育和再生。我们的长期目标是使用一种新的方法， 操纵细胞分泌内源性BMP以促进颅面骨发育。第一步 为了达到这个目标，确定离子通道对BMP信号传导的作用机制， 哺乳动物在这个建议中，我们使用Kir2.1钾（K+）通道来确定分子连接 离子传导性和BMP信号之间的联系。Kir2.1突变的人类和小鼠 先天性颅面缺陷，包括腭裂、牙齿缺陷和小颌畸形，这表明， 通道在颅面发育中起重要作用。目的1确定Kir2.1在BMP中的作用位置 在哺乳动物中使用上位性和拯救实验的途径。目的2检验离子通道 调节哺乳动物的BMP分泌，就像调节苍蝇一样。在其他细胞类型中，离子通道影响细胞内 钙调节分泌。在目标3中，我们确定细胞内钙如何影响BMP释放。的 拟议的实验将为未来的研究奠定基础，利用离子通道的潜力， 刺激组织生长和再生。