MOLECULAR GENETICS OF RED CELL RH ANTIGENS

红细胞 RH 抗原的分子遗传学

• 批准号: 6302330
• 负责人: CHEN-HAN HUANG
• 金额: $ 23.65万
• 依托单位: NEW YORK BLOOD CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-15 至 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6302330
• 关键词: RNA splicing; blood chemistry; blood group antigens; clinical research; erythrocyte membrane; gene expression; gene mutation; gene rearrangement; genetic mapping; genetic polymorphism; genetic recombination; genetic transcription; human genetic material tag; human subject; introns; laboratory rabbit; membrane activity; molecular cloning; molecular pathology; nucleic acid sequence; perinatal blood group incompatibility; phenotype; protein structure function; structural genes; surface antigens; tissue /cell culture

Rh antigens reside in Rh polypeptides of the red cell membrane and form one of the most complex polymorphisms in humans. They are clinically important, accounting for the most common incompatibility found in blood transfusion and hemolytic disease of the newborn. They appear to be essential membrane components because red cells devoid of all Rh antigens (Rh/null phenotype) manifest stomatocytosis, shortened in vivo survival, and multiple membrane abnormalities. Our objectives are to unravel the structure/function relationships of the Rh system and delineate the genetic mechanisms for its phenotypic diversity. The specific aims are: 1) To clone and map the entire RH locus and establish the physical order and transcriptional direction of its gene members. 2) To determine the molecular basis of different Rh antigens and phenotypes with emphasis on how DNA recombination and other genetic mechanisms modulate gene structure and cause antigenic variation. 3) To study the expression of a novel Rh transcript that may characterize the d (D-negative) haplotypes and determine the mechanism that results in its activation. 4) To study differential splicing of the Rh genes and determine its role in the onset and regulation of Rh gene expression during erythroid development. 5) To identify the Rh/null and Rhmod genes and determine whether the primary defect is in the Rh genes themselves or in the Rh-related candidate genes. The proposed studies promise to provide insights into structure/function relationships of Rh proteins and the genetic mechanisms leading to one of the most polymorphic human systems. The knowledge gained will deepen our understanding of clinical problems associated with blood transfusion and hemolytic reactions and provide a basis for the clinical service to use molecular approaches in transfusion medicine.

Rh抗原存在于红细胞膜的Rh多肽中， 人类最复杂的多态性之一 他们在临床上 重要的是，占血液中发现的最常见的不相容性 输血和新生儿溶血病。 他们似乎是 由于红细胞缺乏所有Rh抗原， (Rh/无效表型）表现出气孔增多，缩短了体内存活， 和多处膜异常 我们的目标是解开 Rh系统的结构/功能关系，并描绘 表型多样性的遗传机制。 具体目标是： 1)克隆和绘制整个RH基因座并建立物理顺序 以及其基因成员的转录方向。 2)确定 不同Rh抗原和表型的分子基础，重点是 DNA重组和其他遗传机制如何调节基因结构 并引起抗原变异。 3)研究一种新的Rh 可能表征d（D阴性）单倍型的转录物， 确定导致其激活的机制。 4)研究 Rh基因的差异剪接，并确定其在发病中的作用 以及红系发育过程中Rh基因表达的调控。 5)到 鉴定Rh/null和Rhmod基因，并确定是否主要的 缺陷是在Rh基因本身或在Rh相关的候选基因。 拟议的研究有望提供对结构/功能的见解 Rh蛋白质的关系和遗传机制，导致一个 最具多态性的人类系统。 所获得的知识将加深我们的 了解与输血相关的临床问题， 溶血反应，为临床服务使用提供依据 输血医学中的分子方法