Clinical Investigations Of Sjogren s Syndr

干燥综合征(SS)是一种自身免疫性疾病，其特征是外分泌腺和其他器官广泛发炎，导致身体衬里表面干燥，最明显的是口干和眼干。此外，它还可以累及许多其他器官，如关节、皮肤和神经系统。在该项目下，GTTB-SS诊所进行临床调查和临床试验，并与GTTB、其他NIH实验室和NIH以外的机构的实验室调查人员合作，以了解这种疾病的发病机制。我们研究的最终目标是寻找治疗干燥S综合征(SS)的安全、有效和有针对性的具体步骤。为了实现这一目标，我们将研究集中在两大类。自然病史研究包括观察性和回溯性研究，目的是扩大我们对SS发病机制的了解，改进我们的诊断和预后工具，并确定新疗法的靶点。另一个主要领域涉及对干燥综合征患者的新治疗方法的评估。 自上次报告以来，任命了一名新主任并扩大了干燥综合征诊所，这导致SS诊所的组织结构发生了很大变化。随着两位优秀的风湿病研究员的到来，临床活动逐渐增加。临床活动主要集中在自然历史研究和新方案的开发上。与GTTB的其他实验室合作，我们建立了一个项目，系统地评估免疫调节在干燥综合征患者和动物模型中的效果。这一合作努力的目标是缩小基础科学和临床实践之间的差距。要实现这一点，从患者那里获得具有良好特征的高质量临床数据是至关重要的。为此，我们启动了一项计划，将主要以硬拷贝和各种小型电子格式提供的大量与患者相关的研究数据转化为一个灵活、强大、用户友好的电子关系数据库。最终的系统还将使患者和卫生保健提供者能够将数据直接输入电子数据库，从而显著提高疗效。 在实验室方面，我们继续正在进行的合作，并开始了一些新的项目。为了确定干燥S综合征(SS)患者唾液中的生物标志物，我们与人类颅面遗传学实验室合作，采用蛋白质组学方法分析了39例SS患者和19例正常对照的蛋白质表达谱。我们发现SS组的β2-微球蛋白、乳铁蛋白、免疫球蛋白轻链和多聚体Ig受体显著增加。在疾病的各个阶段都出现了增加。两种不匹配的蛋白质，可能是富含脯氨酸的蛋白质和淀粉酶在患者组中减少。与对照组相比，干燥S综合征患者的唾液蛋白质组图谱反映了炎症活动和腺泡损伤的增加。这些结果表明，高通量蛋白质组学方法可以用来发现腮腺唾液中SS的生物标志物。 我们努力的另一个主要领域是评估干燥综合征的新疗法。最终目标是开发针对SS发病机制特定步骤的安全有效的治疗方法。我们的一般方法是从早期临床研究(I/II阶段)开始，以确定介入的安全性，同时收集有关其可能有效性的数据。我们的目标是了解为什么一种针对免疫系统特定成分的特定药物可能起作用，也可能不起作用。因此，我们将结合这些临床试验和深入的基础科学评估，进一步了解SS的发病机制和干预的生物学效应。舍格伦？S诊所的主要目标是进行转化性研究，这些研究在较小的研究中可以达到最好的效果，包括在多中心环境下可能不切实际的机械性研究。我们已经确定了几种可能用于这些研究的药物，并计划在明年开始几项临床试验。

Sjogren's Syndrome (SS) is an autoimmune disease, characterized by widespread inflammation in the exocrine glands and other organs resulting in dryness of the lining surfaces of the body, most notably, dry mouth and dry eyes. In addition it can involve numerous other organs such as the joints, skin and nervous sytem. Under this project, the GTTB- SS Clinic conducts clinical investigations and clinical trials, and collaborates with laboratory investigators in GTTB, other NIH laboratories and Institutions outside the NIH in order to understand the mechanisms underlying this disease. The ultimate goal of our research is to find treatments for Sjogren?s Syndrome (SS) that are safe, effective and target specific steps in the pathogenesis of SS. To achieve this goal, we focus our research in two broad categories. Natural history studies include observational and retrospective studies with the goal to expand our knowledge about the pathogenesis of SS, to improve our diagnostic and prognostic tools and to identify targets for new therapies. The other major area involves the evaluation of novel treatments in patients with Sjogren's Syndrome. The period since the last reporting was marked by the appointment of a new Head and expansion of the Sjogren's Syndrome Clinic leading to considerable changes in the organization of the SS Clinic. Clinical activities have increased gradually with arrival of two excellent rheumatology reseach fellows during the year. The clinical activities focused primarily on the natural history studies and on the develoment of new protocols. In collaboration with other laboratories in GTTB we established a program to sytematically evalute the effect of immunomodulation in both patients and animal models of Sjogren's Syndrome. The goal of this collaborative effort is to narrow the gap between basic science and clinical practice. To achieve this, it is essential to have well characterized, high quality clinical data from patients. To this effect we have started a program to transform the large amount of patient-related research data available primarily in hardcopies and in various small electronic formats into a single flexible, powerful, user-friendly electronic relational database. The final system will also enable direct entry of data by patients and health care providers into the electronic database, significantly improving efficacy. On the laboratory side we have continued on-going collaborations and started some new projects. To identify biomarkers of Sjogren?s Syndrome (SS) in the saliva,we analyzed protein expression profiles of 39 SS patients and 19 controls by by proteomic methods, in collaboration with the laboratory of Human Craniofacial Genetics (NIDCR). We identified significant increases of beta 2-microglobulin, lactoferrin, immunoglobulin light chain and polymeric Ig receptor in the SS group. Increases were present in all stages of disease. Two unmatched proteins, presumably proline-rich proteins, and amylase were reduced in the patient groups. The salivary proteomic profile of Sjogren?s Syndrome patients reflected both increased inflammatory activity and acinar damage when compared to controls. These results indicate that high-throughput proteomic approaches can be used to discover biomarkers of SS in parotid saliva. The other major area of our efforts focuses on evaluating novel treatments for Sjogren's Syndrome. The ultimate aim is to develop safe and effective treatments that target specific steps in the pathogenesis of SS. Our general approach is to start with early stage clinical studies (Phase I/II) to establish the safety of an intervention, and at the same time, collect data about its possible efficacy. Our goal is to understand why a particular drug targeting specific components of the immune system may or may not work. Therefore, we will combine these clinical trials with thorough basic science evaluations to learn more about the pathogenesis of SS and the biologic effects of the intervention. The main goal of the Sjogren?s Clinic is to perform translational research that can be best achieved in smaller studies including mechanistic studies that may be impractical in a multicenter setting. We have identified several drugs that may be available for these studies and plan to start several clinical trials in the next year.