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: 9135824
• 负责人: Emily Bates
• 金额: $ 38.57万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-23 至 2017-09-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9135824
• 关键词: Affect; Alcohols; Alleles; Antiepileptic Agents; Apoptosis; Arrhythmia; Binding; Biological Assay; Bone Development; Bone Morphogenetic Proteins; Bone Regeneration; Bone Transplantation; Cardiac Myocytes; Cartilage; Cells; Cephalic; Cleaved cell; Cleft Palate; Craniofacial Abnormalities; Data; Defect; Dental; Development; Developmental Biology; Developmental Process; Disease; Drosophila genus; Ear; Ectoderm; Embryo; Environmental Risk Factor; Foundations; Future; Genetic; Goals; Growth; Growth Factor; Health; Homologous Gene; Homologous Protein; Human; Immigration; Inborn Genetic Diseases; Ion Channel; Ions; Knockout Mice; Limb structure; Lip structure; Mammalian Cell; Mammals; Mediating; Micrognathism; Molecular; Mus; Mutation; Natural regeneration; Neural Crest; Neural Crest Cell; Neurons; Neurosciences; Orbital separation excessive; Palate; Paralysed; Patients; Pharmaceutical Preparations; Phenotype; Play; Potassium; Potassium Channel; Process; Production; Protein Secretion; Publishing; Role; Secondary Palate; Signal Transduction; Specific qualifier value; Specificity; Stem cells; Stimulus; Striated Muscles; Structure; Syndrome; Teratogens; Testing; Tissues; Tooth structure; Trauma; Undifferentiated; Work; bone; cell type; controlled release; craniofacial; craniofacial development; experience; fetal; fly; insight; novel strategies; novel therapeutic intervention; osteoblast differentiation; reconstruction; research study; scaffold; small molecule; success; tissue regeneration; transcriptome sequencing; tumor; voltage

 DESCRIPTION (provided by applicant): 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. Our hypothesis is that ion channel activity regulates BMP secretion in mammals in a conserved mechanism. 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. We recently discovered that ion channels control the secretion of BMP in the fruit fly. The first step towards this goal is to determine how ion channels contribute to craniofacial development in mammals. In this proposal, we use the Kir2.1 potassium (K+) channel to determine the molecular connection between ion conductivity and developmental 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 defines the developmental processes in palate closure that require Kir2.1 (proliferation, apoptosis, palate shelf fusion, differentiation, and/or ossification) and tests the hypothesis that Kir2.1 modulates BMP signaling in mice. Aim 2 identifies the cell types that require Kir2.1 for palate development. In Aim 3, we manipulate ion channel function to test the hypothesis that cellular depolarization can increase BMP secretion. The proposed experiments will lay a new foundation for future studies to harness the potential of ion channels in non- excitable cells to stimulate tissue growth and regeneration.

 描述（由申请人提供）：创伤、肿瘤和颅面疾病后需要进行颅面重建。骨移植和合成支架的成功有限。骨形态发生蛋白 (BMP) 刺激骨和软骨的生成，是牙齿发育、腭闭合和正常颅面发育所必需的。 BMP 也是骨骼修复所必需的，并且可以刺激干细胞承担软骨和骨骼的命运。我们的假设是离子通道活性以保守的机制调节哺乳动物中的 BMP 分泌。如果我们的假设被证明是正确的，那么影响离子通道活性的电刺激或小分子可能能够控制 BMP 的释放，以促进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操纵细胞分泌内源性 BMP 的新方法来促进颅面骨的发育。我们最近发现离子通道控制果蝇中 BMP 的分泌。实现这一目标的第一步是确定离子通道如何促进哺乳动物颅面发育。在本提案中，我们使用 Kir2.1 钾 (K+) 通道来确定哺乳动物中离子电导率和发育信号之间的分子联系。 Kir2.1 突变的人和小鼠患有先天性颅面缺陷，包括腭裂、牙齿缺陷和小颌畸形，这表明该通道在颅面发育中发挥着重要作用。目标 1 定义了需要 Kir2.1 的腭闭合发育过程（增殖、凋亡、腭架融合、分化和/或 骨化）并测试 Kir2.1 调节小鼠 BMP 信号传导的假设。目标 2 确定上颚发育需要 Kir2.1 的细胞类型。在目标 3 中，我们操纵离子通道功能来检验细胞去极化可以增加 BMP 分泌的假设。拟议的实验将为未来的研究奠定新的基础，以利用非兴奋性细胞中离子通道的潜力来刺激组织生长和再生。