The Skeleton of Lateral Meningocele Syndrome

项目摘要/摘要 Notch受体在细胞命运的决定以及成骨细胞和破骨细胞的调控中起着关键作用。 分化和功能。因此，Notch受体在骨重建中起着重要的作用。 尽管这一功能是毋庸置疑的，但大多数调查都探讨了Notch1和Notch1的行动 最近Notch2。NOTCH3是由骨骼细胞表达的，但它在成骨细胞和成骨细胞的命运和功能中的作用 破骨细胞是未知的。外侧脑膜膨出综合征(LMS)是一种毁灭性的疾病，其特征是 脑膜膨出、头面部发育异常和骨质丢失。LMS与基因突变有关 NOTCH3的外显子33位于PEST结构域的上游，导致NOTCH3稳定，并可能导致- 功能。这项拟议的研究的目的是表征独特的和最近创建的小鼠模型 LMS以了解LMS涉及的骨骼疾病和机制。因此，它的功能 骨架中的NOTCH3也将被定义。我们的具体目标是：目标1)描述一个新创建的 全球Notch3LMS突变小鼠模型。全球Notch3LMS突变体的骨骼表型将是 与接触照相测定的野生型性别匹配产仔鼠相比， 密度测量、显微CT扫描和组织形态计量学。实验动物骨骼的生物力学特性 将对LMS突变小鼠进行分析，并探索导致表型的机制；目标2) 确定Notch3LMS突变的细胞谱系特异性效应。为此，我们创建了Notch3LMS Cre重组后重建LMS突变的条件性反转(COIN)模型。我们的 具体的目标是创建针对成骨细胞谱系的细胞的突变，以确定它们对 LMS的骨骼表现；目的3)建立LMS的发病机制。 骷髅。我们将确定Notch3LMS的细胞中Notch3的mRNA和蛋白是否稳定 解释观察到的表型的突变体，以及LMS表型是否需要Notch3激活。 我们将确定Notch正则信号通路是否与LMS表型和 抗Notch3抗体能否逆转Notch3LMS突变表型。

PROJECT SUMMARY/ABSTRACT Notch receptors play a critical role in cell fate decisions and in the regulation of osteoblast and osteoclast differentiation and function. As a consequence, Notch receptors play an important role in bone remodeling. Whereas this function is unquestionable, most of the investigations have explored the actions of Notch1 and recently Notch2. Notch3 is expressed by skeletal cells, but its role in the fate and function of osteoblasts and osteoclasts is unknown. Lateral Meningocele Syndrome (LMS) is a devastating disease characterized by meningoceles, craniofacial developmental abnormalities and bone loss. LMS is associated with mutations in exon 33 of NOTCH3 upstream of the PEST domain leading to NOTCH3 stabilization and presumably gain-of- function. The aim of the proposed research is to characterize unique and recently created mouse models of LMS to understand the skeletal disease and mechanisms involved in LMS. As a consequence, the function of Notch3 in the skeleton also will be defined. Our specific aims are: Aim 1) To characterize a newly created global Notch3LMS mutant mouse model. The skeletal phenotype of global Notch3LMS mutants will be compared to that of wild type sex-matched littermate mice and determined by contact radiography, densitometry, micro CT scanning and histomorphometry. The biomechanical properties of the skeleton from LMS mutant mice will be analyzed and mechanisms responsible for the phenotype will be explored; Aim 2) To determine cell lineage specific effects of the Notch3LMS mutation. To this end, we created a Notch3LMS conditional by inversion (COIN) model that recreates the LMS mutation following Cre recombination. Our specific goals are to create mutants specific to cells of the osteoblast lineage to determine their contribution to the skeletal manifestations of LMS; and Aim 3) To establish the mechanism responsible for LMS in the skeleton. We will determine whether Notch3 mRNA and protein are stabilized in cells from Notch3LMS mutants explaining the phenotype observed, and whether Notch3 activation is required for the LMS phenotype. We will determine whether the Notch canonical signaling pathway is responsible for the LMS phenotype and whether the Notch3LMS mutant phenotype can be reversed by the administration of anti-Notch3 antibodies.