Mouse Models for Elastic Fiber Diseases

弹性纤维疾病小鼠模型

• 批准号: 7866691
• 负责人: MON-LI H. CHU
• 金额: $ 17.21万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7866691
• 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

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）：本资助的目标是为人类弹性纤维系统疾病生成新的小鼠模型。已知细胞外弹性纤维网络的定量和定性变化与一系列影响心血管、肺、骨骼、眼和皮肤系统的先天性和退行性疾病有关。细胞外基质蛋白纤维蛋白-4最近被发现是一种对弹性纤维组装至关重要的分子。该蛋白与tropoelastin和fibrin -1相互作用，其缺乏导致小鼠弹性纤维形成受损和TGF-2信号传导增加。近年来，在临床表现为主动脉瘤、肺动脉狭窄、动脉弯曲、肺气肿、先天性骨折、关节松弛和皮肤松弛的人类患者中发现了纤维蛋白-4的错义突变。这些发现表明，纤维蛋白-4具有多效性，具有广泛的作用，纤维蛋白-4的氨基酸变异可能是动脉瘤、肺气肿和骨质疏松症等复杂疾病的危险因素。本应用程序拟产生两种小鼠模型，其中包含最近在患者中发现的不同错义纤维蛋白-4突变。这些错义突变将被引入小鼠胚胎干细胞，用于产生杂合和纯合的小鼠突变体。这些模型将有助于更深入地了解由纤维蛋白-4错义突变引起的疾病的分子基础和发病机制。未来，这些小鼠突变体可以与其他弹性纤维成分的小鼠模型一起繁殖，从而能够研究纤维蛋白-4和其他关键弹性纤维成分的差异和重叠功能。小鼠模型也将为与弹性纤维功能障碍相关的复杂疾病的病因和发病机制提供新的见解。这些小鼠模型的可用性是评估弹性纤维疾病治疗策略的核心。公共卫生相关性：该应用程序建议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可导致主动脉瘤、肺气肿、骨折和皮肤松弛。小鼠模型的生成对这些疾病的治疗性治疗的发展至关重要。