Function of Fibulins

描述（申请人的描述）：纤蛋白是一个新兴的家族， 细胞外基质蛋白，其特征在于存在串联阵列， 钙结合表皮生长因子样模块和一个共同的C-末端 球状域迄今已确定五名成员，他们属于 两个小组。前两个成员，fibulin-1和-2，与 通过序列同一性和模块化结构， 最近描述的成员，fibulin-3，-4和-5。所有纤维蛋白，除了 纤蛋白-3在心脏和血管壁中高度丰富，因此可以 在心血管系统中发挥重要作用。我们的实验室第一 鉴定了fibulin-2，并随后广泛研究了fibulin-1和-2。 我们和其他人已经表明，fibulin- 1和-2是主要的组成部分， 心脏隔膜和瓣膜以及主动脉、肺动脉和各种大的 和小血管。纤维蛋白-1和-2也被证明存在于 血管壁的弹性纤维， 血管内皮抑制素，血管生成抑制剂。在胚胎发育过程中，fibulin-1 和-2是内皮间充质和平滑肌的高度特异性标志物 各种类型的血管细胞。flbulin-1的表达模式 和-2重叠，但存在明显的时间和空间差异。一 fibulin-1在血管形成中的关键作用被我们的研究所证实。 最近的研究表明，缺乏fibulin- 1的小鼠在围产期是致命的， 大出血的结果。在这次续约申请中，我们计划继续 利用生物化学方法研究fibulin-1和fibulin-2的生物学作用 方法和转基因小鼠产生的基因打靶，并开始 研究细胞类型特异性 控制纤蛋白基因的表达。此外，我们建议使用 以flbulin-1和flbulin-2基因为标记，详细研究心脏的发育 隔膜和瓣膜、大血管和冠状血管。拟议 这些研究将深入了解纤蛋白在人类疾病中的作用， 心血管发育的机制。

DESCRIPTION (applicant's description): The fibulins are an emerging family of extracellular matrix proteins characterized by the presence of tandem arrays of calcium-binding epidermal growth factor-like modules and a common C-terminal globular domain. Five members have been identified to date and they belong to two subgroups. The first two members, fibulin-1 and -2, are more related to each other by sequence identity and modular structure than to the three recently described members, fibulin-3, -4 and -5. All fibulins, except for fibulin-3, are highly abundant in the heart and blood vessel walls and thus may play essential roles in the cardiovascular system. Our laboratory first identified fibulin-2 and has subsequently studied fibulin-1 and -2 extensively. We and others have shown that fibulin- 1 and -2 are prominent components of heart septa and valves as well as aorta, pulmonary artery, and various large and small blood vessels. Fibulin-1 and -2 have also been shown to be present in the elastic fibers of the blood vessel walls where they colocalize with endostatin, the angiogenesis inhibitor. During embryonic development, fibulin-1 and -2 are highly specific markers for endocardial mesenchyme and smooth muscle cells of various types of blood vessels. The expression patterns of flbulin-1 and -2 overlap but there are distinct temporal and spatial differences. A critical role for fibulin-1 in blood vessel formation is demonstrated by our recent work showing that mice lacking fibulin- 1 are perinatally lethal as a result of massive bleeding. In this renewal application, we plan to continue studying the biological roles of fibulin-1 and fibulin-2 using biochemical approaches and transgenic mice generated by gene targeting, and to begin investigating the molecular mechanisms by which the cell-type specific expressions of fibulin genes are controlled. In addition, we propose to use flbulin-1 and -2 genes as markers to study in detail the development of heart septa and valves, great vessels and coronary blood vessels. The proposed studies will provide insights into the role of fibulins in human disease and the mechanism of cardiovascular development.