Mechanisms defining microfibril and elastic fibre assembly, structure and function.

弹性纤维在动脉、肺和皮肤等提供弹性的组织中非常重要。正常结构和功能的破坏是常见疾病的主要方面，如动脉粥样硬化、动脉瘤、心脏瓣膜脱垂、肺气肿和先天性疾病马凡综合征。弹性纤维由蛋白质弹性蛋白的核心组成，周围环绕着12 nm的糖蛋白微纤维。在发育过程中，微原纤维总是出现在弹性蛋白之前，似乎是其前体原弹性蛋白沉积的支架。然而，对每种糖蛋白在微纤维和弹性纤维的组装、结构、功能和细胞生物学中的作用的了解仍然非常有限。我们的实验室已经识别、克隆和鉴定了几种微纤维蛋白，我们处于独特的地位，可以利用我们的专业知识和独特的研究工具来阐明上述过程中涉及的机制。其具体目的是确定a)单个成分和相关蛋白质在微纤维和弹性纤维生物学中的作用，b)微纤维的结构及其结构异质性与组织发育过程中功能的关系，c)微纤维和弹性纤维组装以及其他微纤维与细胞表面相互作用的机制，d)控制单个微纤维蛋白表达的基因调控机制，以及e)非纤维蛋白基因在马凡样先天性疾病中的致病突变。这项研究将极大地增加我们对微纤维组装和弹性纤维形成所涉及的复杂分子机制的控制因素的基础知识，包括单个微纤维相关蛋白的作用、细胞表面受体、细胞加工以及这些过程在正常发育过程中的基因调控，这在理解弹性纤维在重大疾病中的全部作用之前是必不可少的。

Elastic fibres are important in tissues such as arteries, lung and skin where they provide elasticity. Disruption of their normal structure and function is a major aspect of common diseases such as atherosclerosis, aneurisms, heart valve prolapse, emphysema, and the congenital disorder, Marfan syndrome. Elastic fibres consist of a core of the protein elastin surrounded by 12 nm glycoprotein microfibrils. During development the microfibrils always appear before the elastin and seem to act as a scaffold for the deposition of its precursor, tropoelastin. However knowledge of the role of each glycoprotein in the assembly, architecture, function and cell biology of microfibrils and elastic fibres is still very limited. Our laboratory has identified, cloned and characterised several microfibrillar proteins and we are uniquely placed to exploit our expertise and unique range of research tools to elucidate the mechanisms involved in the above processes. The Specific Aims are to determine a) the roles of individual components and associated proteins in microfibril and elastic fibre biology b) the architecture of microfibrils and the relationship of their structural heterogeneity to function during tissue development, c) the mechanisms responsible for microfibril and elastic fibre assembly, and other microfibril interactions with the cell surface, d) the gene regulatory mechanisms controlling expression of individual microfibrillar proteins and e) causative mutations of non-fibrillin genes in Marfan-like congenital disorders. The research will greatly increase our fundamental knowledge of the factors controlling the complex molecular mechanisms involved in microfibril assembly and elastic fibre formation, including the roles of individual microfibril-associated proteins, cell surface receptors, cellular processing, and gene regulation of these processes during normal development, which is essential before the full role of elastic fibres in major diseases can be understood.