Novel Mouse Model for Junctional Epidermolysis Bullosa

新型小鼠交界性大疱性表皮松解症模型

基本信息

批准号：
8035421
负责人：
JOHN Paul SUNDBERG
金额：
$ 19.41万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8035421
关键词：
Affect Age Alleles Birth Bulla Candidate Disease Gene Chromosomes, Human, Pair 19 Congenic Strain Data Dental Enamel Dental Enamel Hypoplasia Dermal Disease Epidermolysis Bullosa Epithelial Functional disorder Gene Proteins Genes Genetic Genetic Variation Goals Haplotypes Human Inbred Strains Mice Intervention Junctional Epidermolysis Bullosa Knock-out LAMC2 gene Lesion Life Life Style Maps Modeling Molecular Morbidity - disease rate Mouse Strains Murine leukemia virus Mus Mutant Strains Mice Mutation Pathway interactions Patients Pattern Perinatal Pharmacologic Substance Phenotype Physiologic calcification Predisposition Proteins Public Health Quantitative Trait Loci RNA Splicing Resistance Risk Rodent Model Screening procedure Severities Skin Symptoms Testing Therapeutic Therapeutic Intervention Time Transcript Ulcer Variant Work base clinical effect congenic design early onset human disease infant death mouse model mutant novel outcome forecast pre-clinical premature prognostic public health relevance resistant strain skin disorder therapeutic development tool

项目摘要

DESCRIPTION (provided by applicant): Epidermolysis Bullosa (EB) is a devastating, heritable blistering skin disease characterized by widespread epithelial fragility, blistering, and ulceration. Rodent models that faithfully recapitulate EB-like skin diseases are sorely needed to understand the underlying genetics of EB and to develop therapeutic interventions. We identified a novel, spontaneous, autosomal recessive, hypomorphic mutation in the gene Lamc2, which results in mice that progressively develop a blistering skin disease throughout their life that is remarkably similar to human generalized non-Herlitz junctional epidermolysis bullosa (JEB). Our Lamc2jeb homozygous mutant mice faithfully recapitulate the pathological features of the human disease, including progressive dermal/epidermal separation, tooth enamel hypoplasia, lowered bone mineralization, dyspenia, and premature morbidity. Importantly, our preliminary data show that the strain background onto which the Lamc2jeb mutant allele is introgressed can have remarkably strong effects on the severity of JEB. Thus, genetic modifier loci can determine whether mice succumb to devastating disease or are minimally affected. We propose to elucidate the genetic basis of this differential susceptibility. Our overall hypothesis is that allelic variants of certain modifier genes have a major impact in controlling the phenotypic severity of JEB. To test this hypothesis, our first goal is to define quantitative trait locus (QTL) patterns for genetic modifiers of JEB. We will perform QTL analyses of crosses between resistant and susceptible mouse strains to identify the QTL(s) responsible for these effects. Our second goal is to fine map major QTL intervals to identify candidate gene(s). We identified a major Chromosome 19 modifier QTL that affects the time of onset of skin blistering in a 129X1/SvJ X DBA/1J F2-Lamc2jeb/Lamc2jeb cross. We will use a combination of congenic reduction, subphenotypic, and haplotype analyses to hone-in on the genes responsible for the Chromosome 19 QTL and possibly others that emerge. These studies will make it possible to ascribe functional attributes to QTLs that increase or reduce risk for JEB in our mouse model, to suggest the candidate gene(s) responsible, and to characterize their mechanism(s) of action. Overall, the work will open the door for assessment of whether the same genes, encoded proteins, and associated pathways pose risk in human JEB patients and for designing therapeutic approaches based on the modifier gene effects or even as primary pharmaceutical targets. PUBLIC HEALTH RELEVANCE: We have developed mice carrying a spontaneous mouse mutation that is an important preclinical tool for understanding why junctional epidermolysis bullosa (JEB) develops in humans. Characterization of the genetic basis of JEB in this unique model promises to identify novel prognostic tools, pharmacological targets, and, once the mechanism is understood, potential ways to modify lifestyle to moderate the clinical effects of JEB in humans.

描述（由申请人提供）：表皮溶解Bullosa（EB）是一种毁灭性的，可遗传的皮肤疾病，其特征是普遍的上皮脆弱性，起泡和溃疡。非常需要忠实地概括类似EB的皮肤疾病的啮齿动物模型，以了解EB的潜在遗传学并开发治疗性干预措施。我们确定了一种新颖的，自发的，常染色体隐性的，肌肌肌的肌肌肌肌肌张力，这导致小鼠在一生中逐渐发展出一种与人类广义的非her- herlitz联合性表皮分解bulo（jeb）非常相似的小鼠。我们的LAMC2JEB纯合突变小鼠忠实地概括了人类疾病的病理特征，包括进行性皮肤/表皮分离，牙齿搪瓷发育不全，降低骨骼矿化，抑制性和早产。重要的是，我们的初步数据表明，LAMC2JEB突变等位基因的应变背景对JEB的严重程度产生非常强大的影响。因此，遗传修饰基因座可以确定小鼠是否屈服于毁灭性疾病或受到最小的影响。我们建议阐明这种差异性的遗传基础。我们的总体假设是，某些修饰符基因的等位基因变体在控制JEB的表型严重程度方面具有重大影响。为了检验这一假设，我们的第一个目标是为JEB的遗传修饰者定义定量性状基因座（QTL）模式。我们将对抗性和易感小鼠菌株之间的杂交进行QTL分析，以识别负责这些效应的QTL。我们的第二个目标是详细地图QTL间隔，以识别候选基因。我们确定了一个主要的染色体19修饰剂QTL，该染色体会影响129x1/svj x DBA/1J F2-LAMC2JEB/LAMC2JEB Cross中皮肤起泡的时间。我们将结合使用先天性减少，亚表型和单倍型分析，以磨练负责染色体19 QTL以及可能出现的其他可能的基因。这些研究将使在小鼠模型中增加或降低JEB风险的QTL将功能属性归因于QTL，以提出负责任的候选基因并表征其作用机制。总体而言，这项工作将为评估人JEB患者的相同基因，编码蛋白质和相关途径的风险以及基于修饰剂基因效应还是设计治疗方法的相同基因和相关途径的风险打开大门。公共卫生相关性：我们开发了携带自发小鼠突变的小鼠，这是理解为什么交界表皮溶液Bullosa（JEB）在人类中发展的重要临床前工具。 JEB在这种独特模型中的遗传基础的表征有望识别新颖的预后工具，药理学靶标，一旦理解了机制，可以改变生活方式的潜在方法，以调节JEB在人类中的临床影响。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Molecular identification of collagen 17a1 as a major genetic modifier of laminin gamma 2 mutation-induced junctional epidermolysis bullosa in mice.

DOI：
10.1371/journal.pgen.1004068
发表时间：
2014-02
期刊：
PLoS genetics
影响因子：
4.5
作者：
Sproule TJ;Bubier JA;Grandi FC;Sun VZ;Philip VM;McPhee CG;Adkins EB;Sundberg JP;Roopenian DC
通讯作者：
Roopenian DC