Basement Membrane Biosynthesis

描述(申请人提供)：基底膜是薄的冷凝物 位于上皮细胞、周围肌肉下的特殊细胞外基质 细胞，并服务于各种生理功能。它们的病理化学 在几种疾病以及普通医学的发展中都很重要 和衰老。它们的合成和修饰还不是很清楚。我们证明了 人和人的基底膜的一些主要成分非常相似 果蝇，建立了研究基底膜形成的方法学 果蝇，以及在胚胎细胞培养中对已知蛋白质的分化 底物，并证明了这种可遗传的系统的效用。我们 首先在果蝇中发现了新的基底膜蛋白，后来发现了它们的 人、小鼠和线虫中的同源物，特别是Papin和Peroxasin。 这两种蛋白质对果蝇胚胎发育都是必不可少的。停止，或 过度表达，木瓜素的合成扰乱了几个正常的细胞排列 器官，但不是细胞分化。罂粟碱存在于大多数果蝇和 小鼠基底膜。 结缔组织的合成和分解涉及分泌型ADAMTS 金属蛋白酶，如前胶原N-蛋白水解酶(ADAMTS2)处理胶原 前体和聚集聚糖酶(ADAMTS4)可切割几种基质成分。ADAMTS 酶和Papilins共享一个同源蛋白结构域的盒，并且 互动。我们将研究这种相互作用如何本地化、调制和 控制果蝇的ADAMTS功能和器官发生，其中我们 鉴定出三种ADAMTS酶，并在小鼠体内。 小鼠过氧化物酶基因在各器官中广泛分布。我们将会问是否 小鼠过氧化物酶是一种有效的过氧化物酶，它是否发生在地下室 膜和吞噬巨噬细胞，就像果蝇一样。它可能会在 防御和/或连接组织。我们对纸浆和纸浆的研究 过氧化物酶对结缔组织病理生物学有影响。

DESCRIPTION (provided by applicant): Basement membranes are thin condensations of specialized extracellular matrix that underlie epithelia, surround muscle cells, and serve various physiological functions. Their pathological chemistry is important in several diseases, as well as in general medicine, development and aging. Their synthesis and modifications are not understood.We showed that some major constituents of basement membranes are very similar in man and Drosophila, established methodology for studying basement membrane formation in Drosophila, and in embryo cell cultures differentiating on known protein substrates, and proved the utility of this genetically accessible system. We found new basement membrane proteins first in Drosophila and later their homologues in man, mouse and nematode, specifically Papilin and Peroxidasin. Both proteins are essential for Drosophila embryogenesis. Stopping, or overexpressing, papilin synthesis disrupt normal cell arrangements of several organs, but not cell differentiation. Papilin occurs in most Drosophila and mouse basement membranes. Connective tissue synthesis and breakdown involve secreted ADAMTS metalloproteases, e.g. procollagen N-proteinase (ADAMTS2) processes a collagen precursor and aggrecanase (ADAMTS4) cuts several matrix components. ADAMTS enzymes and Papilins share a cassette of homologous protein domains, and interact. We shall investigate how such interactions may localize, modulate and control ADAMTS functions and organogenesis in Drosophila, in which we identified three ADAMTS enzymes, and in mice. Mouse Peroxidasin mRNA is widely distributed among organs. We shall ask whether mouse peroxidasin is a working peroxidase, and whether it occurs in basement membranes and phagocytic macrophages, as it does in Drosophila. It may serve in defense and/or in connecting tissues. Our investigations of Papilin and Peroxidasin have implications for connective tissue pathobiology.