Molecular Basis of Tooth Eruption

牙齿萌出的分子基础

基本信息

批准号：
6606422
负责人：
GARY E WISE
金额：
$ 29.4万
依托单位：
LOUISIANA STATE UNIV A&M COL BATON ROUGE
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-07-01 至 2008-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): To help determine the molecular basis of tooth eruption, this proposal will focus on how a requirement of eruption, osteoclastogenesis, is regulated at the molecular level. The dental follicle (DF), a loose connective tissue sac that surrounds the unerupted tooth, recruits mononuclear cells to the follicle where they fuse to form osteoclasts necessary to form an eruption pathway. A molecule produced by the DF, colony-stimulating factor-1 (CSF-1), is required for tooth eruption. Another molecule found in the DF, osteoprotegerin (OPG), inhibits osteoclastogenesis. In the first mandibular molar of the rat or mouse, the maximal number of osteoclasts is present either at day 3 (rat) or day 5 (mouse) on the alveolar bone, a time that correlates with maximal gene expression of CSF-1 in the adjacent follicle and minimal gene expression of OPG. It is postulated that the downregulation of OPG expression allows the maximal osteoclastogenesis and that this decrease in OPG expression is regulated by CSF-1. To test this hypothesis, osteopetrotic mice that have impaired CSF-1 production and inhibited tooth eruption will be examined to determine if OPG expression in the DF remains elevated at day 5, in contrast to its reduced expression in normal mice. Because injections of CSF-1 accelerate the time of eruption, it will be determined if such injections also reduce OPG gene expression. Conversely, injections with OPG will be done to determine if increased levels of OPG delay or inhibit eruption in normal mice and rats. Laser-capture microdissection techniques will be employed to resolve in what dental tissues of the rat receptor activator of nuclear factor-kappaB ligand is expressed to actively promote osteoclast formation. The final aim will determine what molecules may be involved in the secondary minor burst of osteoclastogenesis seen at day 10 postnatally in the 1st mandibular molar. Real-time PCR and microarray techniques will determine what genes are maximally expressed in the DF at this time. In vitro studies will determine if such gene products can support osteoclast formation. Understanding the molecular regulation of osteoclastogenesis during eruption may explain why impacted teeth (e.g., 3rd molars) do not erupt, as well as explain the causes of various eruption disorders. A molecular approach to induce eruption is a long-term goal. In addition, understanding the molecular basis of bone resorption may aid in determining what factors cause alveolar bone loss such as is seen in periodontitis.

描述（由申请人提供）：为了帮助确定牙齿萌出的分子基础，该提案将重点关注如何在分子水平上调节萌出的要求（破骨细胞生成）。牙囊 (DF) 是围绕未萌出牙齿的疏松结缔组织囊，它将单核细胞募集到毛囊，在那里它们融合形成形成萌出途径所需的破骨细胞。牙齿萌出需要 DF 产生的分子，即集落刺激因子 1 (CSF-1)。 DF 中发现的另一种分子是骨保护素 (OPG)，可抑制破骨细胞生成。在大鼠或小鼠的第一下颌磨牙中，破骨细胞的最大数量出现在第 3 天（大鼠）或第 5 天（小鼠）的牙槽骨上，该时间与牙槽骨中 CSF-1 的最大基因表达相关。邻近卵泡和 OPG 基因表达最小。据推测，OPG 表达的下调允许最大程度的破骨细胞生成，并且 OPG 表达的这种减少受到 CSF-1 的调节。为了检验这一假设，将对 CSF-1 产生受损并抑制牙齿萌出的骨石小鼠进行检查，以确定第 5 天时 DF 中的 OPG 表达是否仍然升高，而正常小鼠中的 OPG 表达却降低。由于注射 CSF-1 会加速出疹时间，因此将确定此类注射是否也会降低 OPG 基因表达。相反，注射 OPG 以确定 OPG 水平的增加是否会延迟或抑制正常小鼠和大鼠的出疹。将采用激光捕获显微切割技术来解析核因子-κB配体的大鼠受体激活剂在哪些牙组织中表达，以积极促进破骨细胞形成。最终目标将确定哪些分子可能参与出生后第 10 天在下颌第一磨牙中观察到的二次小破骨细胞生成爆发。实时 PCR 和微阵列技术将确定此时 DF 中哪些基因表达最大。体外研究将确定此类基因产物是否可以支持破骨细胞的形成。了解萌出过程中破骨细胞生成的分子调节可以解释为什么阻生牙（例如第三磨牙）不萌出，以及解释各种萌出疾病的原因。诱导喷发的分子方法是一个长期目标。此外，了解骨吸收的分子基础可能有助于确定哪些因素导致牙槽骨丢失，例如牙周炎中所见的情况。