MOLECULAR BIOLOGY OF THE HUMAN H & SE BLOOD GROUP GENES

这项工作的总体目标是确定监管机制 哺乳动物低聚糖分子的表达。岩藻糖化 寡糖被选为实验模型是因为它们的 岩藻糖键和同源岩藻糖基转移酶 它们的生物合成，在时间和空间上都有精确的表达 在哺乳动物分化过程中，并经常在 与恶变有关。这些属性表明 这些分子的重要功能；这是最近才发现的 通过研究表明，特定集合中的一个或多个成员 岩藻糖化低聚糖，由髓系细胞表达， 介导这些白细胞与内皮细胞的黏附 炎症过程中的分子I。此外，其中许多岩藻糖基化 寡糖代表其表达由以下因素决定的分子 人类血型基因。 为了解决这些类型分子的表达调控问题，我们 已经分离出编码α(1，2)岩藻糖基转移酶的人类基因。 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 鉴定其他类似的α(1，2)岩藻糖基转移酶基因，包括 分泌者血型轨迹。此外，这些基因代表了 阐述转录和转录后调控 决定……类型和相对数量的考虑因素 由组织和细胞制成的α(1，2)岩藻糖化糖偶联物。一个 对这些过程的理解将有助于增加 了解这些分子在正常人体内的功能 组织和恶性转化的组织中。 这项建议的具体目标是： 1.分离编码新的人类基因 α(1，2)岩藻糖基转移酶或其他决定基因 利用基因转移方法表达这种酶。 2.分离和鉴定符合以下条件的人类DNA序列 在结构上与人类H血型相似 α(1，2)岩藻糖基转移酶基因。 3.确定H血型的生物合成 α(1，2)岩藻糖基转移酶等 可在特定AIMS中分离的α(1，2)岩藻糖基转移酶1 2.利用生物化学、分子遗传学和形态学 接近了。 4.确定人类遗传多态的分子基础 分泌者血型轨迹。 5.确定α(1，2)岩藻糖基转移酶的表达模式 人类正常组织中的基因。

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.