MOLECULAR BIOLOGY OF THE HUMAN H & SE BLOOD GROUP GENES

这项工作的总体目标是确定调节机制， 哺乳动物寡糖分子的表达。 基化 选择低聚糖作为实验模型，因为它们 岩藻糖键，和同源岩藻糖转移酶负责 它们的生物合成，以时间和空间的精确性表达， 在哺乳动物的分化过程中， 与恶性转化有关。 这些特性表明， 这些分子的重要功能;这是最近才发现的 研究表明，一组特定的 岩藻糖基化低聚糖，由髓系细胞表达， 介导这些白细胞与内皮白细胞的粘附 分子I在炎症中的作用。 此外，许多这些岩藻糖基化 寡糖代表其表达由以下决定的分子： 人类血型基因 为了解决这些类型的分子表达的调节，我们 已经分离出编码α（1，2）岩藻糖基转移酶的人基因。 该基因被认为与H血型基因座相对应。 这 基因，以及用于分离它的技术，代表了 为了鉴定其他这样的α（1，2）岩藻糖基转移酶基因，包括 分泌型血型位点。 此外，这些基因代表了 解决转录和转录后调节 考虑决定的类型和相对数量 由组织和细胞产生的α（1，2）岩藻糖基化糖缀合物。 一个 了解这些过程将有助于提高 了解这些分子在正常人中的功能 组织和恶性转化的组织中。 本提案的具体目标是： 1. 分离出新的人类基因 α（1，2）岩藻糖基转移酶，或基因，否则决定 使用基因转移方法表达这些酶。 2. 为了分离和表征人类DNA序列， 与人类H血型结构相似 α（1，2）岩藻糖基转移酶基因。 3. 定义H血型的生物合成 α（1，2）岩藻糖基转移酶，以及其它类似酶， 可在特定目的1中分离的α（1，2）岩藻糖基转移酶 第二，利用生物化学、分子遗传学和形态学 接近。 4. 为了明确人类遗传多态性的分子基础， 分泌型血型位点。 5. 确定α（1，2）岩藻糖基转移酶的表达模式 正常人体组织中的基因

The overall goals of this work are to determine mechanisms that regulate expression of mammalian oligosaccharide molecules. Fucosylated oligosaccharides were chosen as an experimental model because their fucose linkages, and the cognate fucosyltransferases responsible for their biosynthesis, are expressed with temporal and spatial precision during mammalian differentiation, and are frequently altered in association with malignant transformation. These properties suggested important functions for these molecules; this has been born out recently by studies demonstrating that one or more members of a specific set of fucosylated oligosaccharides, expressed by cells of the myeloid lineage, mediate adhesion of these leukocytes to endothelial leukocyte adhesion molecule I during inflammation. Moreover, many of these fucosylated oligosaccharides represent molecules whose expression is determined by human blood group genes. To address the regulation of expression of these types of molecules, we have isolated a human gene encoding an alpha(1,2)fucosyltransferase. This gene is thought to correspond to the H blood group locus. This gene, and the techniques used to isolate it, represent tools with which to identify other such alpha(1,2)fucosyltransferase genes, including Secretor blood group locus. Furthermore, these genes represent tools to address transcriptional and post-transcriptional regulatory consideration that determine the types and relative amounts of alpha(1,2)fucosylated glycoconjugates made by tissues and cells. An understanding of these processes will serve to increase the understanding of the functions of these molecules in normal human tissues, and in malignantly transformed tissues. The SPECIFIC AIMS of this proposal are: 1. To isolate novel human genes that encode alpha(1,2)fucosyltransferases, or genes that otherwise determine expression of such enzymes, using gene transfer methods. 2. To isolate and characterize human DNA sequences that are structurally similar to the human H blood group alpha(1,2)fucosyltransferase gene. 3. To define the biosynthesis of the H blood group alpha(1,2)fucosyltransferase, and other such alpha(1,2)fucosyltransferases that may be isolated in Specific Aims 1 and 2, using biochemical, molecular genetic, and morphological approaches. 4. To define the molecular basis for genetic polymorphism at the human Secretor blood group locus. 5. To define the expression patterns of alpha(1,2)fucosyltransferase genes in normal human tissues.