CANDIDATE PROTEIN CLONES IN EB

拟议的计划项目将研究分子的各个方面， 和皮肤基底膜区的细胞生物学。 的目标 该项目的重点是表征潜在的候选蛋白质 大疱性表皮病病理生理学事件的重要性 （EB）。 我们将尝试定义参与这些过程的结构和蛋白质。 基底膜区的功能完整性，并表征 控制其合成、分泌和降解的机制。 的 具体项目如下。 I.“DNA克隆的开发和使用 对于隐性营养不良中潜在重要性的候选蛋白， 隐性连接和获得性EB”将开发和使用探针来映射 基因和建立遗传性EB的多态性，并确定可能的 获得性EB与HLA的关系 二.“角质细胞运动 和蛋白酶表达”将检查附着和迁移行为 的角质形成细胞，并表征金属蛋白酶的库 由迁移的细胞表达。 三.“模型系统的开发 BMZs：真皮微血管基底膜的代谢”将 检测正常和活化内皮细胞的基质蛋白合成 并将这些细胞的行为与 EB患者 四.“慢性损伤，增强蛋白水解和 RDEB中的致癌作用”是基于这样一个概念，即过量的 蛋白水解是了解结缔组织的基础 这是RDEB的特点。 它将探讨的机制， 金属蛋白酶表达的调控在一个三维模型， 再造皮肤 此外，为了了解 在RDEB中发生皮肤癌的倾向增加，RDEB皮肤作为 将检查异种移植物的致癌潜力。 五、“胎儿的创伤” 反应”将表征胎儿皮肤中某些关键的 胎儿期基底膜区蛋白和抗原 发展 胎儿皮肤移植于裸鼠和SCID小鼠的行为学观察 将被确定并与EB皮肤的伤口反应类似地进行比较 嫁接的 六.“角质形成细胞与基底细胞相互作用的生物学 “膜”将决定EB是否影响细胞-细胞或细胞- 基质相互作用，并确定什么样的作用，如果有的话，膜突蛋白，肝素- 结合受体蛋白，可能在这个过程中。 最终，我们希望 这些研究将有助于更好地了解 基底膜区和更有效的治疗方法EB。

The proposed program project will study various aspects of the molecular and cellular biology of the basement membrane zone of the skin. The goals of this project focus on characterizing candidate proteins of potential importance in pathophysiologic events involved in epidermolysis bullosa (EB). We shall attempt to define structures and proteins involved in the functional integrity of the basement membrane zone and to characterize mechanisms governing their synthesis, secretion and degradation. The specific projects are as follows. I. "Development and Use of DNA Clones for Candidate Proteins of Potential Importance in Recessive Dystrophic, Recessive Junctional, and Acquired EB" will develop and use probes to map genes and establish polymorphisms in hereditary EB and define possible relationships between acquired EB and HLA. II. "Keratinocyte Locomotion and Protease Expression" will examine the attachment and migratory behavior of keratinocytes and characterize the repertoire of matalloproteases expressed by the migrating cells. III. "Development of Model Systems for BMZs: Metabolism of the Dermal Microvascular Basement Membrane" will examine matrix protein synthesis by normal and activated endothelial cells and compare the behavior of these cells with that of endothelial cells from patients with EB. IV. "Chronic Injury, Enhanced Proteolysis and Carcinogenesis in RDEB" is predicated on the notion that excessive proteolysis is fundamental to understanding the connective tissue destruction that characterizes RDEB. It will explore the mechanisms of regulation of matalloprotease expression in a 3-dimensional model of reconstituted skin. In addition, in an attempt to understand the basis for an increased propensity to develop skin cancers in RDEB, RDEB skin as a xenograft will be examined for carcinogenic potential. V. "The Fetal Wound Response" will characterize the expression in fetal skin of certain key proteins and antigens of the basement membrane zone during fetal development. The behavior of fetal skin grafted onto nude or SCID mice will be determined and compared to the wound response of EB skin similarly engrafted. VI. "Biology of the Interaction of Keratinocytes with Basement Membranes" will determine whether or not EB affects cell-cell or cell- matrix interactions and determine what role, if any, moesin, a heparin- binding receptor protein, may have in this process. Ultimately, we hope that these studies will lead to better understanding of the function of the basement membrane zone and to more effective therapeutic approaches to EB.