Basement Membrane Biosynthesis

描述（由申请人提供）：基底膜是薄冷凝物 一种特殊的细胞外基质， 细胞，并提供各种生理功能。他们的病理化学 在几种疾病以及一般医学中， 和衰老。它们的合成和修饰尚不清楚。 基底膜的一些主要成分在人类中非常相似， 果蝇，建立了研究基底膜形成的方法， 果蝇，并在胚胎细胞培养分化上的已知蛋白质 底物，并证明了这种遗传可访问系统的实用性。我们 首先在果蝇中发现了新的基底膜蛋白， 人、小鼠和线虫中的同源物，特别是Papilin和Peroxidasin。 这两种蛋白质都是果蝇胚胎发育所必需的。停止或 过度表达，乳头蛋白合成破坏了几种细胞的正常排列， 器官，但不是细胞分化。罂粟蛋白存在于大多数果蝇中， 小鼠基底膜。 结缔组织合成和分解涉及分泌的ADAMTS 金属蛋白酶，例如前胶原N-蛋白酶（ADAMTS 2）加工胶原 前体和聚集蛋白聚糖酶（ADAMTS 4）切割几种基质组分。ADAMTS 酶和乳头蛋白共享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定位、调节和 在果蝇中控制ADAMTS功能和器官发生，其中我们 在小鼠中鉴定了三种ADAMTS酶。 小鼠过氧化物酶mRNA广泛分布于器官中。我们会问， 小鼠过氧化物酶是一种起作用的过氧化物酶， 膜和吞噬巨噬细胞，就像果蝇一样。它可以用于 防御和/或连接组织。我们对Papilin的研究， 过氧化物酶与结缔组织病理生物学有关。

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.