MOLECULAR CHARACTERIZATION OF THE SM SNRNP POLYPEPTIDES

从生物学的角度来看，U1 snRNP是一种普遍存在的核 核糖核蛋白颗粒，在处理中起着至关重要的作用， 前信使RNA。 就人类疾病而言，明显正常的U1 snRNP 颗粒作为体液自身免疫反应的中心焦点 在系统性红斑狼疮中尤为突出， 综合征 例如，最近已经清楚，抗U1 RNP 抗体结合U1 snRNP多肽70 K、A、B ′/B和C，而抗Sm 抗体识别多肽B ′/B和D。 我们已经指示我们的 注意B '/B多肽，因为它们处于 这些回应。 在本项目中，cDNA编码一个或两个密切相关的， B '/B多肽已被克隆和测序。 一位同事，迈克尔博士 Lerner克隆并测序了多肽N的cDNA、大脑和 B ′/B的心脏特异性变体提供了一种潜在的机制， 组织特异性可变mRNA剪接机制。 拟议工作 将识别B ′/B和N上的精确区域， 来自SLE和相关结缔组织病患者的抗体， 将这些区域与B '/B和N中发生的结构变化相关联 在进化过程中。 这些努力将允许测试的假设， 进化稳定性的程度是自身抗原性的主要决定因素。 表位 比较B '/B和N上自身抗原表位的能力 提供了发现自身免疫反应的可能性， 产生于特定组织。 这项工作的重要性在于，它将提供有关 snRNP的U系列结构以及它们如何进化。 而且 精确识别最突出和最有特点的 SLE的自身抗原表位，结合对 提名他们的自身免疫反应，将提供基础， 未来的研究将直接评估选择的“自身”抗原 与免疫系统细胞上的特定表面受体相互作用。

From a biological point of view the U1 snRNP is a ubiquitous nuclear ribonucleoprotein particle that plays a crucial role in the processing of pre-messenger RNA. In terms of human disease, apparently normal U1 snRNP particles act as a central focal point for humoral autoimmune responses that are especially prominent in systemic lupus erythematosus and overlap syndromes. For example it has recently become clear that anti-U1 RNP antibodies bind the U1 snRNP polypeptides 70K, A, B'/B and C while anti-Sm antibodies recognize polypeptides B'/B and D. We have directed our attention to the B'/B polypeptides because they are at the crossroads of these responses. In the present project a cDNA encoding one or both of he closely related B'/B polypeptides has been cloned and sequenced. A colleague, Dr. Michael Lerner, has cloned and sequenced a cDNA for polypeptide N, a brain and heart specific variant of B'/B that provides a potential mechanisms for tissue specific alternative mRNA splicing mechanisms. The proposed work will identify the precise regions on B'/B and N that are recognized by antibodies from patients with SLE and related connective tissue disease and correlate these regions with structural changes that occur in B'/B and N during evolution. These efforts will permit a test of the hypothesis that he degree of evolutionary stability is a major determinant of autoantigenic epitopes. The ability to compare autoantigenic epitopes on B'/B and N offers the potential for discovering autoimmune responses that are generated in specific tissues. The importance of this work is that it will provide new knowledge of the structure of the U series of snRNP and how they evolved. Moreover, the precise identification of the most prominent and characteristic autoantigenic epitopes of SLE, combined with insight into the forces that nominate them for autoimmune responses, will provide the foundation for future studies that will assess directly how selected "self" antigens interact with specific surface receptors on cells of the immune system.