MOLECULAR GENETICS OF SKIN BASEMENT MEMBRANE ZONE IN EB

这份续签申请提出了广泛的研究，重点是 皮肤基底膜带(BMZ)的分子遗传学 不同形式的表皮松解症的分子缺陷 布洛萨(Bullosa)拟议的研究旨在检验这一假设。 在BMZ表达的结构大分子的基因导致了 或更多形式的EB。这项申请是建立在扎实的进展基础上的 过去四年的研究。这一进展的亮点是 包括：(A)克隆编码人类III型胶原的BMZ基因， 大疱性类天疱疮抗原1和2、尼德原和层粘连蛋白A、B1和B2 链序列；(B)5个先前未分配的染色体定位 人类基因组中的BMZ基因；(C)遗传连锁的证明 III型胶原基因座(COL7AI)与显性营养不良 4个锚定纤维缺陷家系的EB突变；(D)遗传 一个显性单纯型EB家系与染色体12Q上一个基因座的连锁 与II型角蛋白基因簇相邻，并定位另一个EB 单纯型家系定位于染色体1q上的一个基因座。这项提议 这些研究的继续需要集中的、多学科的 由参与调查的调查人员进行的研究 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“EB的遗传连锁分析”对规则或规则是至关重要的 排除特定的基因和等位基因作为家系突变的候选基因 和EB一起。项目2“BMZ分子中的遗传缺陷”将提供 关于基因-蛋白质系统中特定突变的准确信息 在各种形式的电子商务中有过错的人。项目3，“转基因小鼠 将引入突变的BMZ基因序列，这些基因序列已经被 在项目2中确定的，进入转基因小鼠，以检查 这种突变的后果。项目4，“第VII类生物学 胶原蛋白“，将集中于阐明细胞的各个方面 III型胶原的分子生物学研究进展 调控蛋白表达的关键蛋白质结构和元件 这个基因。项目5，“BMZ组件的蛋白质和基因结构”， 将提供更多的基因探针和有关正常基因的信息 对项目1、2和3中的研究至关重要的结构。这些 预计多学科研究将提供有关 各种形式的EB的潜在分子缺陷。是这样的 信息对于制定一个明确的 分类，用于开发产前诊断测试，并 为设计新的治疗方法提供了基础 疾病。

This renewal application proposes extensive studies focusing on the molecular genetics of the cutaneous basement membrane zone (BMZ) towards delineating the molecular defects in various forms of epidermolysis bullosa (EB). The proposed studies are designed to test the hypothesis that genes for structural macromolecules expressed at the BMZ cause one or more forms of EB. This application is based on solid progress during the past four years of research. The highlights of this progress include: (a) cloning of BMZ genes encoding human type VII collagen, bullous pemphigoid antigens 1 and 2, nidogen, and laminin A, B1 and B2 chain sequences; (b) chromosomal localization of 5 previously unassigned BMZ genes within the human genome; (c) demonstration of genetic linkage between the type VII collagen gene locus (COL7AI) and dominant dystrophic EB mutations in 4 families with defective anchoring fibrils; (d) genetic linkage of a family with dominant simplex EB to a locus on chromosome 12q adjacent to the type II keratin gene cluster, and mapping of another EB simplex family to a locus on chromosome 1q. The proposal for continuation of these studies entails concentrated, multi-disciplinary studies to be performed by investigators participating in the collaborative research within the Jefferson Institute of Molecular Medicine. The five component projects are highly interdependent. Project 1, "Genetic Linkage Analysis of EB", is vital to rule in or rule out specific genes and alleles as candidates for mutation in families with EB. Project 2, "Genetic Defects in BMZ Molecules", will provide precise information on the specific mutations in the gene-protein systems that are at fault in various forms of EB. Project 3, " Transgenic Mice with EB", will introduce mutated BMZ gene sequences, which have been identified in Project 2, into transgenic mice, to examine the consequences of such mutations. Project 4, "Biology of Type VII Collagen", will concentrate on elucidation of various aspects of cellular and molecular biology of type VII collagen towards identification of critical protein structures and elements regulating the expression of this gene. Project 5, "Protein and Gene Structure for BMZ Components", will provide additional gene probes and information about the normal gene structures that are essential for studies in Projects 1, 2 and 3. 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 a definitive classification, for development of prenatal diagnostic tests, and to provide a basis for devising novel therapeutic approaches for this disease.