M3 RECEPTOR: DIAGNOSTIC MARKER FOR SJOGREN'S SYNDROME

M3 受体：干燥综合征的诊断标志物

基本信息

批准号：
6135024
负责人：
MICHAEL G HUMPHREYS-BEHER
金额：
$ 10万
依托单位：
IXION BIOTECHNOLOGY, INC.
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-01 至 2001-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6135024
关键词：
autoantibody autoimmune disorder biomarker cell line clinical research diagnosis design /evaluation diagnostic tests enzyme linked immunosorbent assay female human subject immunopathology diagnosis lacrimal disorder mucus salivary disorder transfection xerophthalmias xerostomias

项目摘要

Sjogren's syndrome is a human autoimmune disease of the salivary and lacrimal glands resultIng in debilitating xerostomia (dry mouth) and xerophthalmia (dry eyes). This disease may present as either a primary autoimmune disease or as a secondary autoimmune disease concomitant with other connective tissue diseases or diabetes. Although classified as an orphan disease, it is grossly under-diagnosed; thus, it is estimated that as many as 2-4 million individuals (90% of which are women) actually have a form of the disease. At present, diagnosis of Sjogren's syndrome involves detection of lymphocytic infiltrates in biopsies of the labial glands, the presence of autoantibodies to rheumatoid factor and cellular components (e.g., SS-A/Ro, SS-B/La, alpha-fodrin and nuclear material), hypergammaglobulinemia, and loss of exocrine gland flow rates following stimulation. None of these markers is, by itself, disease specific. Recently, we and others have shown that all sera from patients with confirmed Sjogren's syndrome contain an autoantibody to the muscarinic cholinergic-3 receptors (M3) expressed on exocrine gland cells. This finding presents the possibility that this single marker may be able to define autoimmune exocrinopathy. Thus, we propose to investigate the feasibility of developing a simple, non-invasive diagnostic test capable of identifying patients with Sjogren's syndrome. Specific aims of this phase STTR grant are i) to determine if Sjogren's syndrome patients can be identified specifically and universally with an ELISA test using a full-length recombinant form of the M3 protein, and 2) compare the results from ELISA testing with those obtained utilizing a M3-expressing, transfected COS-7 cell line. If results of this study confirm and expand our preliminary data, then final development of a simple, non-invasive, Sjogren's syndrome-specific diagnostic test would be a welcome addition to the clinical diagnostic laboratory and the patient. PROPOSED COMMERCIAL APPLICATIONS: Identification of autoantibodies against the muscarinic acetylcholine-3 receptor (M3) on exocrine gland cells now appears to be the best single marker of autoimmunity in Sjogren's syndrome (autoimmune exocrinopathy). While Sjogren's syndrome is classified an orphan disease, it is also recognized as being under-diagnosed; thus, there may be perhaps 2-4 million patients in the US, 90% of which are women. Development of a non-invasive diagnostic test based on detection of M3 autoantibody would be a major advancement for the clinical laboratory.

干燥综合征是一种人类唾液腺和泪腺自身免疫性疾病，导致衰弱性口干症（口干）和干眼症（眼干）。该疾病可以表现为原发性自身免疫性疾病或伴随其他结缔组织疾病或糖尿病的继发性自身免疫性疾病。尽管被归类为孤儿病，但其诊断率却严重不足。因此，据估计，实际上有 2-400 万人（其中 90% 是女性）患有这种疾病。目前，干燥综合征的诊断包括检测唇腺活检中淋巴细胞浸润、类风湿因子自身抗体和细胞成分（例如 SS-A/Ro、SS-B/La、α-胞质蛋白和核物质）的存在。）、高丙种球蛋白血症和刺激后外分泌腺流速降低。这些标记物本身都不是疾病特异性的。最近，我们和其他人发现，来自确诊干燥综合征患者的所有血清都含有针对外分泌腺细胞上表达的毒蕈碱胆碱能 3 受体 (M3) 的自身抗体。这一发现提出了这种单一标记物可能能够定义自身免疫性外分泌病的可能性。因此，我们建议研究开发一种能够识别干燥综合征患者的简单、非侵入性诊断测试的可行性。此阶段 STTR 资助的具体目的是 i) 确定是否可以通过使用 M3 蛋白全长重组形式的 ELISA 测试来特异性和普遍地识别干燥综合征患者，以及 2) 将 ELISA 测试的结果与获得的结果进行比较利用表达 M3 的转染 COS-7 细胞系。如果这项研究的结果证实并扩展了我们的初步数据，那么最终开发出一种简单、非侵入性、干燥综合征特异性诊断测试将受到临床诊断实验室和患者的欢迎。拟议的商业应用：目前，外分泌腺细胞上针对毒蕈碱乙酰胆碱 3 受体 (M3) 的自身抗体的鉴定似乎是干燥综合征（自身免疫性外分泌病）自身免疫的最佳单一标志物。虽然干燥综合征被归类为孤儿病，但它也被认为诊断不足。因此，美国可能有2-400万患者，其中90%是女性。开发基于 M3 自身抗体检测的非侵入性诊断测试将是临床实验室的重大进步。