GOLGI COMPLEX ANTIBODIES AND AUTOANTIGENS

高尔基复合体的自身抗体主要在干燥综合征和系统性红斑狼疮患者中发现，尽管它们并不局限于这些疾病。这种竞争性更新申请要求为继续研究高尔基复合体的自身抗原并解决导致这些细胞内细胞器相关蛋白的自身抗体表达的机制提供资金。P.I.S实验室一直负责鉴定一种被称为高尔基体的高尔基体抗原家族。这些自身抗原的共同特征是它们位于高尔基池的细胞质表面，它们具有多个α螺旋盘状杆状结构域，两侧是非盘状螺旋结构域和C-末端结构域。这项拟议研究的目的是确定该蛋白家族成员的共同结构和功能是否能够解释疾病状态下自身抗体的起源和产生。特殊目标1将研究高尔基蛋白的共同特征，这可能解释为什么它们是人类抗高尔基体抗体的目标。P.I.将描述与高尔基复合体和高尔基体相关的事件，以及它们在凋亡和坏死过程中的稳定性。关于这些自身抗体如何在实验模型中产生的假设将被检验。特定目标2将检查高尔基体片段和囊泡结构是否会在实验小鼠中诱导免疫和自身免疫反应。具体目标3将阐明高尔基复合体在乳酸脱氢酶提升病毒(LDV)感染小鼠中的靶点，并阐明这些小鼠如何产生对高尔基复合体的自身免疫反应的机制。早期的研究表明，LDV感染的小鼠会产生抗高尔基体抗体。我们目前的数据表明，对细胞质细胞器(如高尔基复合体)的自身免疫反应与迄今所研究的其他细胞内自身抗原是独特的不同。预计对P.I.S假说的检验将为自身免疫和与亚细胞细胞器相关的自身免疫性疾病提供新的见解。

Autoantibodies to the Golgi complex are found primarily in patients with Sjgren's syndrome and SLE although they are not restricted to these diseases. This competitive renewal application requests funding for the continuation of studies to characterize autoantigens of the Golgi complex and address the mechanisms that lead to the expression of autoantibodies to these intracellular organelle-associated proteins. The P.I.'s laboratory has been responsible for the identification of a family of Golgi antigens known as golgins. Common features of these autoantigens are that they are located on the cytoplasmic face of the Golgi cisternae and they have multiple alpha-helical coiled-coil rod domains flanked by non-coiled-coil and C- terminal domains. The goal of the proposed studies is to determine if the common structure and function for members of this protein family can explain the origin and production of autoantibodies in disease states. Specific Aim 1 will examine common features of golgins that may explain why they are targets of human anti-Golgi autoantibodies. The P.I. will characterize the events associated with the Golgi complex and golgins and their stability during apoptosis and necrosis. Hypotheses on how these autoantibodies may be produced in experimental models will be examined. Specific Aim 2 will examine if Golgi fragments and vesicular structures will induce immune and autoimmune response in experimental mice. Specific Aim 3 will elucidate the target of Golgi complex in lactate dehydrogenase-elevating virus (LDV) infected mice and address mechanism of how autoimmune response to the Golgi complex can be produced in these mice. Earlier studies have shown that LDV infected mice produce anti-Golgi antibodies. Our current data suggest that the autoimmune response to cytoplasmic organelles such as the Golgi complex is uniquely different from other intracellular autoantigens examined to date. It is anticipated that testing of the P.I.'s hypotheses will provide new insights into autoimmunity and autoimmune diseases associated with subcellular organelles.