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Targeting the Notch3 Mutation to Cure Lehman Syndrome

针对 Notch3 突变来治愈雷曼综合症

基本信息

批准号：
9901099
负责人：
Ernesto Canalis
金额：
$ 40.3万
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：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9901099
关键词：
Affect Alleles Antisense Oligonucleotides Antisense Technology Award Bone remodeling Cell Line Cells Clinical DNA Sequence Alteration Development Disease Down-Regulation Exhibits Exons Gene Mutation Genes Genetic Diseases Goals Human In Vitro Intervention Knowledge Lateral Lead Liver Mendelian disorder Meningocele Molecular Abnormality Mus Mutant Strains Mice Mutation NOTCH3 gene Osteoblasts Osteoclasts Osteopenia Other Genetics Peripheral Nervous System Phase Phenotype Play Positioning Attribute Proteins Regulation Research Retina Role Secondary to Skeleton Syndrome TRANCE protein Testing Ubiquitination Work bone bone loss cell behavior cortical bone craniofacial effective intervention efficacy study gain of function human disease human model in vivo induced pluripotent stem cell mouse model mutant notch protein novel strategies novel therapeutic intervention osteoclastogenesis premature prevent skeletal skeletal disorder substantia spongiosa

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 plays an important role in bone remodeling. Lehman Syndrome or Lateral Meningocele Syndrome is a devastating disease characterized by craniofacial developmental abnormalities, bone loss and meningoceles. The syndrome is associated with mutations in exon 33 of NOTCH3 upstream of the PEST domain leading to NOTCH3 stabilization and presumably gain-of- function. We created a mouse model of Lehman Syndrome (Notch3tm1.1Ecan) that presents with osteopenia due to enhanced osteoclastogenesis secondary to an increase in receptor activator of nuclear factor Kappa B ligand (RANKL) expression by cells of the osteoblast lineage. The aim of the proposed research is to develop ways to correct the skeletal manifestations of the disease by targeting the mutation with Notch3 antisense oligonucleotides (ASO), a strategy that would be applicable to other genetic disorders of the skeleton. Our specific aims are: Phase R61 Aim 1) To establish the efficacy of Notch ASOs in vitro and in vivo. In this initial aim, we will test whether Notch3 can be downregulated in the skeleton and reverse the skeletal phenotype of Notch3tm1.1Ecan mice; Aim 2) To establish that the Notch3tm1.1Ecan mutation can be targeted. We will determine whether the Notch3tm1.1Ecan mutation can be downregulated specifically and the Notch3tm1.1Ecan skeletal phenotype reversed by the administration of Notch36691-TAATGA antisense oligonucleotides; and Phase R33 Aim 3) To validate the ASO approach in NOTCH3 mutant-induced pluripotent (iPS) cells. In the R33 phase, we intend to prove the utility of Notch3 ASOs in human cells by creating mutant iPS cell lines to study the efficacy of Notch3 ASOs in downregulating NOTCH3 mutant alleles. The goals of the proposed work are to develop specific antisense technology to treat skeletal manifestations of a devastating NOTCH3-associated disease, as an initial step in the treatment of genetic disorders of the skeleton.

项目总结/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节中起着关键作用分化和功能。因此，Notch在骨重建中起着重要作用。雷曼综合征或外侧脑膜膨出综合征是一种毁灭性的疾病，其特征是颅面发育异常骨质流失和脑膜膨出该综合征与基因突变有关， PEST结构域上游的NOTCH 3的外显子33导致NOTCH 3稳定化，并可能导致功能我们建立了一个雷曼综合征（Notch3tm1.1Ecan）的小鼠模型，继发于核因子κ B受体激活剂增加的破骨细胞生成增强配体（RANKL）表达的成骨细胞谱系。该研究的目的是开发通过用Notch 3反义靶向突变来纠正疾病的骨骼表现的方法寡核苷酸（阿索），这是一种适用于骨骼其他遗传疾病的策略。我们具体目的是：R61期目的1）在体外和体内确定Notch ASO的功效。在该初始我们将测试Notch 3是否可以在骨骼中下调，并逆转骨骼表型。 Notch3tm1.1Ecan小鼠;目的2）确定Notch3tm1.1Ecan突变可以被靶向。我们将确定 Notch3tm1.1Ecan突变是否可以特异性下调，Notch3tm1.1Ecan骨骼肌通过施用Notch 36691-TAATGA反义寡核苷酸逆转的表型;和 3)在N 0 TCH 3突变体诱导的多能（iPS）细胞中验证阿索方法。在R33阶段，我们我打算通过创建突变iPS细胞系来研究Notch 3 ASO在人细胞中的功效， Notch 3反义寡核苷酸下调NOTCH 3突变等位基因。拟议工作的目标是发展特异性反义技术治疗破坏性NOTCH 3相关疾病的骨骼表现，治疗骨骼遗传疾病的第一步。