The Skeleton of Lateral Meningocele Syndrome

侧脑膜膨出综合征的骨骼

基本信息

批准号：
9899095
负责人：
Ernesto Canalis
金额：
$ 44.17万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-18 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9899095
关键词：
Address Affect Age Antibodies Biomechanics Bone remodeling Cell Lineage Cell physiology Cells Clinical Densitometry Development Diagnostic radiologic examination Disease Exhibits Exons Experimental Models Funding Genetic Recombination Goals Investigation Knowledge Laboratories Lateral Lead Mediating Meningocele Messenger RNA Modeling Mus Mutant Strains Mice Mutation NOTCH3 gene National Institute of Arthritis and Musculoskeletal and Skin Diseases Neurologic Symptoms Osteoblasts Osteoclasts Osteocytes Osteopenia Pathogenesis Pathway interactions Phenotype Play Positioning Attribute Property Proteins Regulation Research Role Signal Pathway Signal Transduction Skeleton Structure Syndrome Work X-Ray Computed Tomography bone bone loss cortical bone craniofacial gain of function mRNA Decay microCT mouse model mutant mutant mouse model notch protein osteoclastogenesis premature prevent receptor sex skeletal skeletal disorder substantia spongiosa virtual

项目摘要

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.

项目摘要/摘要 Notch受体在细胞命运决策以及成骨细胞和破骨细胞的调节中起关键作用分化和功能。结果，缺口受体在骨骼重塑中起着重要作用。尽管此功能是毫无疑问的，但大多数调查都探讨了Notch1和最近Notch2。 Notch3由骨骼细胞表达，但其在成骨细胞的命运和功能中的作用和破骨细胞是未知的。外侧脑膜元综合征（LMS）是一种毁灭性疾病，其特征是脑膜脑，颅面发育异常和骨质流失。 LMS与突变有关 Notch3的外显子33害虫域的上游导致Notch3稳定，并可能获得功能。拟议研究的目的是表征独特的鼠标模型 LMS了解LMS涉及的骨骼疾病和机制。结果，骨骼中的Notch3也将被定义。我们的具体目的是：目标1）表征新创建的全局Notch3LMS突变小鼠模型。全局Notch3LMS突变体的骨骼表型将是与野生型性爱的同窝小鼠相比，通过接触射线照相确定光密度测定法，微CT扫描和组织形态测定法。骨骼的生物力学特性将分析LMS突变小鼠，并将探索负责表型的机制；目标2）确定Notch3LMS突变的细胞谱系特异性效应。为此，我们创建了一个Notch3LMS 通过反转（硬币）模型的条件，可在CRE重组后重现LMS突变。我们的具体目标是创建特定于成骨细胞谱系细胞的突变体，以确定其对 LMS的骨骼表现；目标3）建立负责LMS的机制骨骼。我们将确定Notch3 mRNA和蛋白是否稳定在Notch3LMS的细胞中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规范信号通路是否负责LMS表型和抗Notch3抗体的给药是否可以逆转Notch3LMS突变表型。