MOLECULAR GENETICS OF SKIN BASEMENT MEMBRANE ZONE

本提案是为响应研究补助金而提出的 关于大疱性表皮松解症(EB)和基底的公告 膜带生物学。拟议的研究旨在测试 一种假设，编码基质的基因突变 皮肤基底膜带的结构大分子 导致一种或多种形式的EB。这项提议需要集中精力， 由以下专家进行的多学科研究 不同的科学学科，所有人现在都参与到 杰斐逊分子研究所内的合作研究 医学。这五个组成部分项目高度相互依存。 项目1“临床和超微结构研究”将提供 重要的患者材料和关键的临床信息 患者，皮肤的形态变化，以及 特定抗原的分布，将指导另一方的工作 项目。在项目2“限制的使用”中生成的数据 连锁研究中的片段长度多态 排除或排除特定的基因和等位基因作为候选 对于将在项目中更详细地探索的变化 3和4.项目3，“生物合成中的遗传缺陷 基底膜区域的大分子“将提供信息 关于可能以各种形式出现故障的基因-蛋白质系统 关于EB的。这个项目的工作，主要集中在 基底膜带结构变化的阐明 因此，蛋白质和信使核糖核酸水平的大分子将提供 有关突变的必要信息，将在 项目4的细节。项目4，“基因表达的突变” 皮肤“将使用分子生物学的技术来定义 准确地说是基因突变。这样的信息将提供 EB变种的一个明确分类基础 在项目1、2和3中确定。项目5，“新的克隆和 在皮肤中表达的基因的结构，“将提供额外的 基因探针和有关正常基因结构的信息 对于项目2、3和4中的研究是必不可少的。这些 多学科研究有望提供准确的 关于各种形式的潜在分子缺陷的信息 关于EB的。这些信息对发展 对这种疾病的明确分类，用于发展 产前诊断试验，并为制定 这种疾病的治疗方法。此外，这些项目 将产生材料、技术和信息 作为未来关于EB和其他方面的研究的永久资源 影响皮肤的遗传性疾病。

The present proposal is submitted in response to research grants announcement in the area of epidermolysis bullosa (EB) and basement membrane zone biology. The proposed studies are designed to test the hypothesis that mutations in the genes that code for the matrix structural macromolecules of the basement membrane zone in skin cause one or more forms of EB. The proposal entails concentrated, multidisciplinary studies performed by experts representing different scientific disciplines and all now participating in collaborative research within the Jefferson Institute of Molecular Medicine. The five component projects are highly interdependent. Project 1, "Clinical and Ultrastructural Studies," will provide the essential patient material and critical clinical information on the patients, the morphological changes in the skin, and the distribution of specific antigens that will guide work on the other projects. The data generated in Project 2, "Use of Restriction Fragment Length Polymorphism for Linkage Studies," are vital to ruling in or ruling out specific genes and alleles as candidates for mutations that will be explored in greater detail in Projects 3 and 4. Project 3, "Genetic Defects in the Biosynthesis of Basement Membrane Zone Macromolecules," will provide information on the gene-protein systems that may be at fault in various forms of EB. The work on this project, primarily concentrating on elucidation of structural alterations in basement membrane zone macromolecules at the protein and mRNA level, will thus provide necessary information about mutations that will be explored in detail on Project 4. Project 4, "Mutations in Genes Expressed in Skin," will use the techniques of molecular biology to define precisely the gene mutations. Such information will then provide a basis for definitive classification of the variants of EB identified in Projects 1, 2 and 3. Project 5, "New Clones and Structures for Genes Expressed in Skin," will provide additional gene probes and information about the normal gene structures that are essential for studies in Projects 2, 3, and 4. These multidisciplinary studies are expected to provide precise information on the underlying molecular defects in various forms of EB. Such information is of critical importance in developing definitive classifications for this disease, for development of prenatal diagnostic tests, and to provide a basis for developing therapeutic approaches for this disease. In addition, the projects will generate materials, technologies and information that can serve as a permanent resource for future studies on EB and other heritable diseases affecting skin.