Mouse Models for Elastic Fiber Diseases

弹性纤维疾病小鼠模型

基本信息

批准号：
7740741
负责人：
MON-LI H. CHU
金额：
$ 20.86万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7740741
关键词：
18 year old 2 year old Affect Alleles Amino Acid Sequence Amino Acids Aneurysm Animal Model Aortic Aneurysm Architecture Arteries Biocompatible Materials Blood Vessels Breeding Calcium Binding Cardiovascular system Clinical Complex Connective Tissue Cutaneous Cutis Laxa Defect Degenerative Disorder Disease Elastic Cartilage Elastic Fiber Embryonic Development Epidermal Growth Factor Etiology Extracellular Matrix Extracellular Matrix Proteins FBN1 Female Fracture Functional disorder Future Gene Targeting Generations Genetic Germ Lines Goals Grant Growth Factor Homeostasis Human Joint Laxity Ligaments Lung Missense Mutation Modeling Molecular Mus Mutant Strains Mice Mutation NIH Program Announcements Organ Osteoporosis Pathogenesis Patients Phenotype Property Proteins Pulmonary Emphysema Pulmonary artery structure Research Risk Factors Signal Pathway Signal Transduction Skin System Tendon structure Tropoelastin Variant age related animal model development artery stenosis base body system embryonic stem cell extracellular fibulin-4 girls homologous recombination human disease in vivo insight mouse model mutant novel public health relevance response skeletal skeletal abnormality therapeutic development therapeutic evaluation transmission process

项目摘要

DESCRIPTION (provided by applicant): The goal of this grant is to generate new mouse models for human diseases of the elastic fiber system. Quantitative and qualitative changes in the extracellular elastic fiber network are known to be associated with a range of congenital and degenerative conditions affecting the cardiovascular, pulmonary, skeletal, ocular and cutaneous systems. The extracellular matrix protein fibulin-4 has recently emerged as a molecule that is essential for elastic fiber assembly. This protein interacts with tropoelastin and fibrillin-1, and its deficiency results in impaired elastic fiber formation and increased TGF-2 signaling in mice. Recently, missense mutations in fibulin-4 have been identified in human patients with clinical manifestations of aortic aneurysm, pulmonary artery stenosis, tortuous arteries, emphysema, congenital bone fractures, joint laxity and cutis laxa. These findings suggest that fibulin-4 is pleiotropic with widespread effects, and that amino acid variations in fibulin-4 may be risk factors for complex diseases, such as aneurysm, emphysema and osteoporosis. This application proposes to generate two mouse models harboring different missense fibulin-4 mutations recently identified in patients. The missense mutations will be introduced into mouse embryonic stem cells, which will be used to generate heterozygous and then homozygous mouse mutants. These models will facilitate a deeper understanding of the molecular basis and pathogenesis of diseases resulting from fibulin-4 missense mutations. The mouse mutants can be bred with mouse models of other elastic fiber components in the future, thereby enabling studies of differential and overlapping functions served by fibulin-4 and other key elastic fiber components. The mouse models will also provide novel insights into the etiology and pathogenesis of complex diseases associated with elastic fiber dysfunction. Availability of these mouse models is central to the evaluation of therapeutic strategies for elastic fiber diseases. PUBLIC HEALTH RELEVANCE: This application proposes to generate mouse models for human diseases of the elastic fiber system. Defects in elastic fibers of the connective tissue can result in aortic aneurysm, lung emphysema, bone fractures and loose skin. Generation of mouse models is central to the development of therapeutic treatment for these disorders.

描述（由申请人提供）：这项资助的目标是为人类弹性纤维系统疾病建立新的小鼠模型。已知细胞外弹性纤维网络的量和质的变化与影响心血管、肺、骨骼、眼和皮肤系统的一系列先天性和退行性疾病有关。细胞外基质蛋白 fibulin-4 最近已成为弹性纤维组装所必需的分子。该蛋白与原弹性蛋白和原纤维蛋白-1 相互作用，其缺陷会导致小鼠弹性纤维形成受损并增加 TGF-2 信号传导。最近，在具有主动脉瘤、肺动脉狭窄、动脉迂曲、肺气肿、先天性骨折、关节松弛和皮肤松弛临床表现的人类患者中发现了fibulin-4的错义突变。这些发现表明，fibulin-4 具有多效性，具有广泛的影响，fibulin-4 的氨基酸变异可能是动脉瘤、肺气肿和骨质疏松等复杂疾病的危险因素。该申请拟生成两种小鼠模型，其中含有最近在患者中发现的不同错义 fibulin-4 突变。错义突变将被引入小鼠胚胎干细胞中，用于产生杂合的小鼠突变体，然后产生纯合的小鼠突变体。这些模型将有助于更深入地了解 fibulin-4 错义突变引起的疾病的分子基础和发病机制。未来，小鼠突变体可以与其他弹性纤维成分的小鼠模型一起培育，从而能够研究 fibulin-4 和其他关键弹性纤维成分的差异和重叠功能。小鼠模型还将为与弹性纤维功能障碍相关的复杂疾病的病因学和发病机制提供新的见解。这些小鼠模型的可用性对于评估弹性纤维疾病的治疗策略至关重要。公共健康相关性：本申请旨在生成人类弹性纤维系统疾病的小鼠模型。结缔组织弹性纤维的缺陷会导致主动脉瘤、肺气肿、骨折和皮肤松弛。小鼠模型的产生对于这些疾病的治疗方法的开发至关重要。