Function of Fibulins

描述(申请人的描述)：腓肠蛋白是一种新兴的 细胞外基质蛋白的特征是存在串联的 钙结合的表皮生长因子样模块和常见的C-末端 球状域。到目前为止，已经确定了五名成员，他们属于 两个亚组。前两个成员，纤毛蛋白-1和-2，与 彼此通过序列同一性和模块化结构比来三个 最近描述的成员是纤毛蛋白-3、-4和-5。所有腓骨蛋白，除了 纤维蛋白-3在心脏和血管壁中含量非常丰富，因此可能 在心血管系统中起着至关重要的作用。我们的实验室首先 鉴定了纤维蛋白-2，并随后对纤维蛋白-1和-2进行了广泛的研究。 我们和其他人已经证明，纤维蛋白-1和-2是 心脏隔膜和瓣膜以及主动脉、肺动脉等各种大血管 和小血管。纤维蛋白-1和-2也被证明存在于 血管壁的弹性纤维与其并存 血管生成抑制因子内皮抑素。在胚胎发育过程中，纤毛蛋白-1 And-2是心内膜间充质和平滑肌的高度特异性标记物 不同类型血管的细胞。Flu蛋白-1的表达模式 和-2重叠，但存在明显的时间和空间差异。一个 我们的研究证实了纤维蛋白-1在血管形成中的关键作用 最近的研究表明，缺乏纤维蛋白-1的小鼠对围产期是致命的 大量出血的结果。在此次续签申请中，我们计划继续 用生化方法研究纤维蛋白-1和纤维蛋白-2的生物学作用 基因打靶产生转基因小鼠的方法和开始 探讨细胞类型特异性的分子机制 纤维蛋白基因的表达受到控制。此外，我们建议使用 FlBulin-1和FlBulin-2基因作为详细研究心脏发育的标志 隔膜和瓣膜，大血管和冠状动脉。建议数 研究将为了解腓肠蛋白在人类疾病中的作用和 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.