Analysis of the Role of Sprouty Genes in Tooth Development

发芽基因在牙齿发育中的作用分析

• 批准号: 7439180
• 负责人: Ophir D Klein
• 金额: $ 12.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7439180
• 关键词: Adult; Affect; Alleles; Ameloblasts; Binding; Biomedical Engineering; Cellular biology; Characteristics; Condition; Defect; Dental; Dentition; Development; Embryo; Embryonic Development; Epithelial; Epithelium; Etiology; Family; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Gene Family; Genes; Genetic; Genotype; Growth; Histologic; Hypersensitivity; Incisor; Kinetics; Knowledge; Lead; Learning; Mandible; Maxilla; Mediating; Mesenchymal; Mesenchyme; Molecular; Morphogenesis; Morphology; Mus; Neural Crest; Numbers; Odontoblasts; Organogenesis; Orthologous Gene; Pathway interactions; Patients; Phenotype; Primordium; Process; Proteins; Public Health; Receptor Protein-Tyrosine Kinases; Regulation; Research; Research Personnel; Role; Shapes; Signal Pathway; Signal Transduction; Signaling Molecule; Stem cells; Supernumerary Tooth; Syndrome; Testing; Tooth Diseases; Tooth structure; Work; adult stem cell; base; craniofacial; gene function; genetic analysis; human disease; inhibitor/antagonist; innovation; insight; member; oral cavity epithelium; postnatal; programs; receptor; research study; stem cell fate; teeth diastema

DESCRIPTION (provided by applicant): The study of the developmental regulation of tooth number and shape is important for understanding human disease. Mammalian tooth development is controlled by signaling between the oral epithelium and the neural crest-derived ectomesenchyme. These interactions are mediated by several signaling pathways, including those activated by Fibroblast Growth Factors (FGFs) via binding to FGF receptor- tyrosine kinases. Members of the Sprouty family modulate FGF signaling by antagonizing it downstream of the receptor. In my previous work, I have shown that inactivation of Spry2 or Spry4 results in the formation of supernumerary teeth in the diastema, a normally toothless region between the incisors and molars of mice. These supernumerary teeth result from hypersensitivity of the odontogenic epithelium or mesenchyme to FGF signaling. In this application, I will pursue the observation that inactivation of multiple Sprouty alleles has profound effects on incisor development. Embryos that are null for Spry4 and heterozygous for Spry2 have supernumerary incisors in the maxilla and remarkable tusk-like incisors in the mandible. Embryos that are null for two Sprouty genes also develop supernumerary incisors, although the morphology of these incisors varies depending on the genotype. The first group of experiments will test the hypothesis that the tusk-like incisor phenotype is caused by effects on stem cells in the adult incisor. I will analyze the role of FGFs and other signaling molecules in regulation of incisor stem cells. The second group of experiments in this proposal is aimed at elucidating the normal mechanisms that control the number and morphology of incisors, as well as the role of Sprouty genes in these processes. Results from these studies will enhance our understanding of the molecular pathways that control epithelial-mesenchymal interactions during tooth organogenesis and may help lead to innovative treatments for patients with dental defects, including even the possibility of bioengineering new teeth. The studies proposed here employ a genetic approach to determine the functions of the Sprouty (Spry) genes in mouse tooth development. Public health implications: By studying the functions of the Sprouty gene family, we will learn more about how teeth normally develop and will understand more about the basis for dental abnormalities. We will also study the role of adult stem cells in teeth, which may help to lay the groundwork for efforts to build new teeth.

描述（由申请人提供）：研究牙齿数量和形状的发育调节对于了解人类疾病具有重要意义。哺乳动物的牙齿发育是由口腔上皮和神经嵴衍生的外间充质之间的信号传导控制的。这些相互作用由多种信号传导途径介导，包括由成纤维细胞生长因子 (FGF) 通过与 FGF 受体酪氨酸激酶结合而激活的信号传导途径。 Sprouty 家族成员通过拮抗受体下游的 FGF 信号来调节 FGF 信号。在我之前的工作中，我已经证明 Spry2 或 Spry4 的失活会导致牙缝中形成多余的牙齿，牙缝是小鼠门牙和臼齿之间通常没有牙齿的区域。这些多余的牙齿是由牙源上皮或间充质对 FGF 信号超敏性产生的。在本申请中，我将观察多个 Sprouty 等位基因的失活对门牙发育具有深远影响。 Spry4 无效且 Spry2 杂合的胚胎在上颌具有多余的门牙，在下颌具有显着的象牙状门牙。两个 Sprouty 基因无效的胚胎也会发育出多余的门牙，尽管这些门牙的形态因基因型而异。第一组实验将检验这样的假设：象牙状门牙表型是由成年门牙干细胞的影响引起的。我将分析 FGF 和其他信号分子在门牙干细胞调节中的作用。该提案中的第二组实验旨在阐明控制门牙数量和形态的正常机制，以及 Sprouty 基因在这些过程中的作用。这些研究的结果将增强我们对牙齿器官发生过程中控制上皮-间质相互作用的分子途径的理解，并可能有助于为牙齿缺陷患者带来创新的治疗方法，甚至包括生物工程新牙齿的可能性。这里提出的研究采用遗传方法来确定 Sprouty (Spry) 基因在小鼠牙齿发育中的功能。公共健康影响：通过研究 Sprouty 基因家族的功能，我们将更多地了解牙齿正常发育的情况，并更多地了解牙齿异常的基础。我们还将研究成体干细胞在牙齿中的作用，这可能有助于为构建新牙齿奠定基础。