Mouse Models for Elastic Fiber Diseases

描述（由申请人提供）：该资助的目标是为弹性纤维系统的人类疾病产生新的小鼠模型。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相关。细胞外基质蛋白fibulin-4最近已经成为一种对弹性纤维组装至关重要的分子。这种蛋白质与原弹性蛋白和纤维蛋白-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。最近，已经在具有主动脉瘤、肺动脉狭窄、迂曲动脉、肺气肿、先天性骨折、关节松弛和皮肤松弛的临床表现的人类患者中鉴定了fibulin-4的错义突变。这些发现表明，fibulin-4是多效性的，具有广泛的影响，并且fibulin-4中的氨基酸变异可能是复杂疾病的危险因素，如动脉瘤、肺气肿和骨质疏松症。本申请提出产生两种小鼠模型，其具有最近在患者中鉴定的不同错义fibulin-4突变。错义突变将被引入小鼠胚胎干细胞，这将用于产生杂合和纯合小鼠突变体。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。在未来，小鼠突变体可以与其他弹性纤维成分的小鼠模型一起繁殖，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。公共卫生相关性：本申请旨在生成弹性纤维系统人类疾病的小鼠模型。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。小鼠模型的产生是开发这些疾病的治疗性治疗的核心。

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.