Clinical Investigations Of Sjogren's Syndrome

干燥综合征的临床研究

基本信息

项目摘要

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 system. Under this project, the MPTB SS Clinic conducts clinical investigations and clinical trials, and collaborates with laboratory investigators in MPTB, 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 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 SS. Natural history studies A major focus of these studies is to evaluate the potential of microRNAs (miRNAs) as biomarkers in SS. We isolated microRNAs from minor salivary glands and saliva and completed miRNA microarray hybridization for 24 tissues and 8 saliva samples. The results allowed us to create a map of microRNAs expressed in minor salivary glands and saliva. Through intensive analysis we identified microRNAs differentially expressed in minor salivary glands from Sjogrens and normal volunteers. We also identified microRNAs differentially expressed in patients with various clinical manifestations. The most promising microRNAs have been validated with TaqMan Quantitative Real Time PCR. Based on our observations about the surprising stability of microRNAs in tissues and saliva when compared to RNA, we explored the use of formalin fixed paraffin embedded tissues as a source of microRNAs. We optimized protocols and successfully isolated microRNAs from paraffin blocks older than thirty years old. This has potentially huge implication since it enables us to use older stored biopsy samples for miRNA analysis. We have continued to expand our DNA bank for patients with SS. This can be used for genetic studies in the future both intramurally and in collaboration with other groups. Currently, we have over 250 DNA samples isolated. In collaboration with the Genomics Branch of NIAMS we published a paper, which, for the first time, has shown that a polymorphism in Stat-4, previously linked to SLE and rheumatoid arthritis, is also associated with SS and may represent a risk factor common to systemic autoimmune diseases. We have also provided DNAs to Dr. John Harleys group in Oklahoma for genome wide association studies in SS. In collaboration with the Neurobiologics and Pain Theraputics Section of NIDCR we tested Sjogrens sera for known and new autoantibodies using a novel highly sensitive immunoprecipitation technology developed in their laboratory. We have shown that this method has a significantly higher sensitivity with as good or better specificity as traditional methods. We also detected antibodies against aquaporin-4 in patients with Sjogrens Syndrome, primarily in those with neurologic manifestations. This observation raises the possibility that anti-AQP4, which is thought to be highly specific for neuromyelitis optica and longitudinal transverse myelitis, may have a role in neurologic manifestations in SS and potentially other autoimmune disorders. Autonomic nervous system (ANS) dysfunction in SS The range of symptoms in SS suggests that there may be perturbations in the nervous and immune systems and in multiple physiological pathways through which these systems communicate and mediate each other. Autoimmunity has been viewed as the most plausible pathogenic mechanism but a significant proportion of patients do not have evidence of systemic autoimmunity, even when followed longitudinally. Compared to normal healthy individuals, SS have significantly more prevalent nervous system involvement including impaired ANS function (which regulates the homeostasis via effects on the smooth muscle, glands and cardiovascular system). However, little is known, about the incidence and prevalence, underlying mechanisms and importance of the ANS in SS patients. In collaboration with the Clinical Neurocardiology Section (NINDS) we started a protocol to investigate ANS function in patients with SS and the association between ANS dysfunction and autoimmunity. We hypothesize that ANS dysfunction is central to the pathogenesis of SS and propose to systematically study the ANS function in our cohort of patients with primary SS compared with normative data from age and sex-matched controls. This protocol consists of a comprehensive evaluation of autonomic function, using physiological, neuropharmacologic, neurochemical, and imaging approaches, to identify consistent distinctive patterns of ANS involvement in SS and thereby improve the diagnosis and understanding of pathophysiologic mechanisms of SS. We have completed testing in 4 subjects. We have also included non-invasive testing of the ANS in the natural history protocol. In the fifty-one SS patients tested sofar we confirmed previous reports of decreased heart rate variability, sympathetic and parasympathetic dysfunction. We also found a paradoxical parasympathetic response to standing which warrants further evaluation in a larger number of patients. MTPB translational research project on Sjogrens Syndrome To narrow the gap between basic science and clinical practice we continued our collaboration with the Adeno-Associated Virus Biology Unit to systematically evaluate the effect of targeted immunomodulation in both patients and animal models of Sjogrens Syndrome. Several projects are underway targeting various molecules, such as TNF alpha, chemokines and anti-M3R antibodies. Our strategy is that by comparing the results from the two approaches we can gain a better understanding of the full therapeutic potential, optimal route of delivery, and biologic impact these molecules may have on the disease. Treatment study using efalizumab (Raptiva) an anti-LFA1 monoclonal antibody Raptiva (efalizumab, Genentech) is an anti-LFA1 monoclonal antibody, which is targeting the LFA1-ICAM pathway that has several functions in Sjogrens Syndrome, including lymphocyte trafficking and antigen presentation. Raptiva is approved for psoriasis but has not been tried in SS yet. During the first three months of the protocol patients are randomized to placebo or Raptiva. This is followed by a 3 month open label phase when everyone receives active drug. Nine patients have been treated in the study, four of which were enrolled during the last year. The protocol uses repeat salivary gland biopsies as part of our response criteria and includes various immunologic assays to address the effect of the treatment on the local and systemic inflammatory process. Future plans We plan to develop several early stage clinical studies (Phase I/II) to establish the safety and toxicity of an intervention, and at the same time, collect data about its possible efficacy. We establish collaborations to combine these clinical trials with thorough basic science evaluations to learn about the pathogenesis of SS and the biologic effects of the intervention. We will continue to collaborate on preclinical studies to enable gene therapy and cellular therapy in the future. In addition to these treatment studies we will do non-interventional clinical studies to address clinical manifestations of Sjogrens Syndrome that are poorly understood and/or not explained by systemic autoimmunity, such as ANS dysfunction and metabolic abnormalities.
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的广泛炎症,导致身体内膜表面干燥,最明显的是口干和眼干。此外,它还可能涉及许多其他器官,如关节、皮肤和神经系统。在这个项目下,MPTB SS诊所进行临床调查和临床试验,并与MPTB、其他NIH实验室和NIH以外的机构的实验室研究人员合作,以了解这种疾病的潜在机制。

项目成果

期刊论文数量(20)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Centromere protein C is a target of autoantibodies in Sjogren's syndrome and is uniformly associated with antibodies to Ro and La.
着丝粒蛋白 C 是干燥综合征自身抗体的靶标,并且与 Ro 和 La 抗体一致相关。
  • DOI:
  • 发表时间:
    2004
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Pillemer,StanleyR;Casciola-Rosen,Livia;Baum,BruceJ;Rosen,Antony;Gelber,AllanC
  • 通讯作者:
    Gelber,AllanC
The clinical impact of neuropsychiatric manifestations in early systemic lupus erythematosus.
早期系统性红斑狼疮神经精神表现的临床影响。
Expanding horizons: modern science enters the mouth.
拓展视野:现代科学传入口中。
Can quantified salivary gland scintigraphy results aid diagnosis of patients with sicca symptoms?
量化的唾液腺闪烁扫描结果可以帮助诊断有干燥症状的患者吗?
Fungal load and candidiasis in Sjogren's syndrome.
干燥综合征中的真菌负荷和念珠菌病。
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Gabor Illei其他文献

Gabor Illei的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Gabor Illei', 18)}}的其他基金

Clinical Investigations Of Sjogren s Syndrome
干燥综合征的临床研究
  • 批准号:
    7318841
  • 财政年份:
  • 资助金额:
    $ 181.02万
  • 项目类别:
Clinical Investigations of Sjogren's Syndrome
干燥综合征的临床研究
  • 批准号:
    8148637
  • 财政年份:
  • 资助金额:
    $ 181.02万
  • 项目类别:
Clinical Investigations of Sjogren's Syndrome
干燥综合征的临床研究
  • 批准号:
    8344131
  • 财政年份:
  • 资助金额:
    $ 181.02万
  • 项目类别:
Clinical Investigations of Sjogren's Syndrome
干燥综合征的临床研究
  • 批准号:
    7967085
  • 财政年份:
  • 资助金额:
    $ 181.02万
  • 项目类别:
Clinical Investigations Of Sj¿gren¿s Syndrome
干燥综合征的临床研究
  • 批准号:
    7593381
  • 财政年份:
  • 资助金额:
    $ 181.02万
  • 项目类别:
Clinical Investigations Of Sjogren s Syndr
干燥综合征的临床研究
  • 批准号:
    7146126
  • 财政年份:
  • 资助金额:
    $ 181.02万
  • 项目类别:

相似国自然基金

靶向递送一氧化碳调控AGE-RAGE级联反应促进糖尿病创面愈合研究
  • 批准号:
    JCZRQN202500010
  • 批准年份:
    2025
  • 资助金额:
    0.0 万元
  • 项目类别:
    省市级项目
对香豆酸抑制AGE-RAGE-Ang-1通路改善海马血管生成障碍发挥抗阿尔兹海默病作用
  • 批准号:
    2025JJ70209
  • 批准年份:
    2025
  • 资助金额:
    0.0 万元
  • 项目类别:
    省市级项目
AGE-RAGE通路调控慢性胰腺炎纤维化进程的作用及分子机制
  • 批准号:
  • 批准年份:
    2024
  • 资助金额:
    0 万元
  • 项目类别:
    面上项目
甜茶抑制AGE-RAGE通路增强突触可塑性改善小鼠抑郁样行为
  • 批准号:
    2023JJ50274
  • 批准年份:
    2023
  • 资助金额:
    0.0 万元
  • 项目类别:
    省市级项目
蒙药额尔敦-乌日勒基础方调控AGE-RAGE信号通路改善术后认知功能障碍研究
  • 批准号:
  • 批准年份:
    2022
  • 资助金额:
    33 万元
  • 项目类别:
    地区科学基金项目
LncRNA GAS5在2型糖尿病动脉粥样硬化中对AGE-RAGE 信号通路上相关基因的调控作用及机制研究
  • 批准号:
    n/a
  • 批准年份:
    2022
  • 资助金额:
    10.0 万元
  • 项目类别:
    省市级项目
围绕GLP1-Arginine-AGE/RAGE轴构建探针组学方法探索大柴胡汤异病同治的效应机制
  • 批准号:
    81973577
  • 批准年份:
    2019
  • 资助金额:
    55.0 万元
  • 项目类别:
    面上项目
AGE/RAGE通路microRNA编码基因多态性与2型糖尿病并发冠心病的关联研究
  • 批准号:
    81602908
  • 批准年份:
    2016
  • 资助金额:
    18.0 万元
  • 项目类别:
    青年科学基金项目
高血糖激活滑膜AGE-RAGE-PKC轴致骨关节炎易感的机制研究
  • 批准号:
    81501928
  • 批准年份:
    2015
  • 资助金额:
    18.0 万元
  • 项目类别:
    青年科学基金项目

相似海外基金

Effect of tea flavonoids and low dose estrogen on bone metabolism in an animal model for age-related bone loss
茶黄酮和低剂量雌激素对年龄相关性骨质流失动物模型骨代谢的影响
  • 批准号:
    488140-2016
  • 财政年份:
    2018
  • 资助金额:
    $ 181.02万
  • 项目类别:
    Postdoctoral Fellowships
The Structural and Metabolic Changes Associated with Ependymal Layer Disruption in the Age Continuum of Hydrocephalus - A Human and Animal Model Study
脑积水年龄连续体中与室管膜层破坏相关的结构和代谢变化 - 人类和动物模型研究
  • 批准号:
    376678
  • 财政年份:
    2017
  • 资助金额:
    $ 181.02万
  • 项目类别:
    Studentship Programs
Effect of tea flavonoids and low dose estrogen on bone metabolism in an animal model for age-related bone loss
茶黄酮和低剂量雌激素对年龄相关性骨质流失动物模型骨代谢的影响
  • 批准号:
    488140-2016
  • 财政年份:
    2017
  • 资助金额:
    $ 181.02万
  • 项目类别:
    Postdoctoral Fellowships
Effect of tea flavonoids and low dose estrogen on bone metabolism in an animal model for age-related bone loss
茶黄酮和低剂量雌激素对年龄相关性骨质流失动物模型骨代谢的影响
  • 批准号:
    488140-2016
  • 财政年份:
    2016
  • 资助金额:
    $ 181.02万
  • 项目类别:
    Postdoctoral Fellowships
Animal model of impaired autoregulation for study of age related vascular cognitive impairment
用于研究年龄相关血管认知障碍的自动调节受损动物模型
  • 批准号:
    9197938
  • 财政年份:
    2016
  • 资助金额:
    $ 181.02万
  • 项目类别:
The domestic cat as an animal model for age-related neurofibrillary tangles
家猫作为年龄相关神经原纤维缠结的动物模型
  • 批准号:
    24780283
  • 财政年份:
    2012
  • 资助金额:
    $ 181.02万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
Identification of candidate genes responsible for an increased susceptibility of age-related macular degeneration using an animal model and its application to gene diagnosis.
使用动物模型鉴定导致年龄相关性黄斑变性易感性增加的候选基因及其在基因诊断中的应用。
  • 批准号:
    22591939
  • 财政年份:
    2010
  • 资助金额:
    $ 181.02万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
MT1-MMP-based Animal Model of Age-related Macular Degeneration (AMD)
基于 MT1-MMP 的年龄相关性黄斑变性 (AMD) 动物模型
  • 批准号:
    8101435
  • 财政年份:
    2008
  • 资助金额:
    $ 181.02万
  • 项目类别:
MT1-MMP-based Animal Model of Age-related Macular Degeneration (AMD)
基于 MT1-MMP 的年龄相关性黄斑变性 (AMD) 动物模型
  • 批准号:
    7481783
  • 财政年份:
    2008
  • 资助金额:
    $ 181.02万
  • 项目类别:
A novel molecular paradigm of age-related macular degeneration in view of the social trend in nocturnal: An approach using an animal model
鉴于夜间活动的社会趋势,年龄相关性黄斑变性的新分子范式:使用动物模型的方法
  • 批准号:
    20791248
  • 财政年份:
    2008
  • 资助金额:
    $ 181.02万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了