CANDIDATE PROTEIN CLONES IN EB

拟议的计划项目将研究分子的各个方面。 以及皮肤基底膜带的细胞生物学。目标 这个项目的重点是鉴定潜在的候选蛋白质 大疱性表皮松解症相关病理生理事件的重要性 (EB)。我们将尝试定义结构和蛋白质参与 基底膜带的功能完整性，并表征 它们的合成、分泌和降解的机制。这个 具体项目如下。我。“DNA克隆的开发和应用 对于在隐性营养不良中具有潜在重要性的候选蛋白质， 隐性连接，和获得性EB将开发和使用探针来作图 遗传性EB基因和多态的建立及可能的定义 获得性EB与人类白细胞抗原的关系二、“角质形成细胞运动” 和蛋白表达“将考察依恋和迁徙行为 角质形成细胞的表达，并鉴定基质蛋白酶谱 由迁移细胞表达。三.“模型系统的开发” BMZ：真皮微血管基底膜的代谢 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来自 EB患者。四、“慢性损伤，增强的蛋白质分解和 RDEB中的致癌作用是建立在过量的 蛋白质分解是理解结缔组织的基础。 破坏是RDEB的特征。它将探索这些机制。 Mat蛋白水解酶表达的三维调控 再造的皮肤。此外，为了了解 在RDEB、RDEB皮肤中发生皮肤癌的倾向增加 将检查异种移植的致癌潜力。五.“胎儿的伤口” 反应“将表征某些键在胎儿皮肤中的表达 胚胎发育过程中基底膜带的蛋白质和抗原 发展。胚胎皮肤移植到裸鼠和SCID小鼠身上的行为 将被测定并与EB皮肤的创伤反应进行类似的比较 被植入了。六、六、角质形成细胞与基底相互作用的生物学 膜“将决定EB是否影响细胞-细胞或细胞- 矩阵相互作用，并确定什么作用，如果有的话，moesin，肝素- 结合受体蛋白，可能在这一过程中起作用。最终，我们希望 这些研究将使我们更好地理解 基底膜带和更有效的治疗EB的方法。

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.