Investigation of Regulatory T Cells in Veterans with Rheumatologic Disease
患有风湿病的退伍军人中调节性 T 细胞的研究
基本信息
- 批准号:8333483
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-07-01 至 2016-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdrenal Cortex HormonesAdverse effectsAdvisory CommitteesAffectAllergicAutoimmune DiseasesAutoimmune ProcessBacteriaBioethicsBiometryBiostatistical MethodsBlood VesselsBrainCD4 Positive T LymphocytesCaringCell surfaceCellsCellular biologyCharacteristicsClinicalClinical ResearchColorCommitCross-Sectional StudiesCytokine SignalingDataDiagnosisDiseaseDoseEffector CellEnsureEnvironmentEpigenetic ProcessEquilibriumFemaleGeneral PopulationGenesGoalsGoldHealthHeartHomeostasisHumanHuman IdentificationsHypersensitivityImmuneImmune System DiseasesImmune systemIn VitroInfectionInflammatoryInterferon Type IInvestigationJointsKidneyLeadLeukocytesLupusLymphocyteMeasuresMediatingMentorsMethodsMolecularMolecular BiologyMusNatureOccupationsOrganPathway interactionsPatientsPersonal SatisfactionPhysiciansPopulationReceptor SignalingRegulationRegulatory T-LymphocyteResearchResearch MethodologyResearch PersonnelResearch TechnicsResearch TrainingRheumatismRoleScientistSeveritiesSignal PathwaySteroid therapySteroidsSuppressor-Effector T-LymphocytesSystemSystemic Lupus ErythematosusT-LymphocyteTestingTrainingTranslational ResearchVeteransVirusWomanWorkbasecytokinedemethylationimprovedinnovationmiddle agenew therapeutic targetnovel markernovel strategiesresponsesystemic autoimmune diseasetrend
项目摘要
DESCRIPTION (provided by applicant):
The proportion of females, in particular women of color, among veterans is increasing. This subset of veterans frequently develops lupus, a devastating systemic autoimmune disease. There is a need to understand the mechanism of lupus, and to train physician-scientists capable of managing this disease using innovative approaches. Recent research findings have suggested that a class of T lymphocytes called regulatory T cells (Tregs) is centrally involved in regulating the immune system in health and disease, including in veterans. Current approaches to identifying Tregs in humans are poorly developed, as FoxP3, the marker of these cells in mice, is not as reliable in humans. Our studies suggest that a new marker, Helios, combined with FoxP3 allows for reliable identification of human Tregs. Helios-positive Tregs are validated as committed Tregs by use of gold standard tests showing that they do not make immune-activating cytokines and also have full demethylation of the FoxP3 gene, in contrast to Helios-negative FoxP3-positive cells, which make cytokines and are only partially FoxP3 gene demethylated. We demonstrate that in patients with more clinically severe systemic lupus erythematosus, there is a trend toward a lower ratio between Helios-positive Tregs and Helios- negative FoxP3-positive cells. In addition, we have found that Helios-positive Tregs increase in direct correlation with steroid therapy in lupus patients with low to moderate clinical severity. Moreover, we have observed that an inflammatory environment high in Type I interferon inhibits regulatory T cells. Based on these observations, we hypothesize that using Helios in combination with FoxP3 for identification of Tregs provides a more reliable method to evaluate immune disturbance and response to therapy. We also hypothesize that Type I interferon suppresses Treg expansion and activation, which is likely reversed by corticosteroids. In the proposed study, we will assess the validity of these hypotheses by addressing the following Specific Aims. In Specific Aim 1, we will validate Helios, in combination with FoxP3, as a definitive marker of natural regulatory T cells by expanding our study of Tregs in a larger number of patients with systemic lupus erythematosus. In Specific Aim 2, we will assert that Type I interferon drives expansion of effector T cells at the expense of regulatory T cells. We wil determine the mechanism by which Type I interferon inhibits regulatory T cells. In Specific Aim 3, cross-sectional analyses will be performed to determine how steroids may promote Treg expansion and possibly reverse the negative effects of Type I interferon. The goal of this research is to improve the well-being of veterans, particularly female veterans, by identifying those lupus patients who could benefit from therapy specifically aimed at stimulating Tregs. By investigating the mechanisms by which Type I interferon suppresses human Tregs and the pathways by which steroids promote human Tregs, we hope to discover new therapeutic targets in the treatment of not only lupus, but also a variety of autoimmune, allergic, and inflammatory disorders prevalent among veterans. Simultaneously, this work will allow the candidate to establish himself as an independent physician-scientist with a research focus in the regulation of the immune system in order to ultimately improve the lives of patients. The training and mentoring plans outline the path toward this goal by proposing a specific plan of coursework in translational research, biostatistics, and bioethics. The proposed research plan will expose the applicant to new research techniques in molecular biology and receptor signaling under the expertise of his primary mentor, Dr. Sergei Atamas. Dr. Violeta Rus, the first co-mentor, will provide clinical and research expertise in the care and study of patients with SLE. Dr. Marc Hochberg, the second co-mentor, will provide guidance in translational research and biostatistical methods. In addition, an advisory committee composed of renowned experts in T cell biology, FoxP3 epigenetics, clinical research, and training of junior investigators will help ensure that the applicant succeeds in becoming an independent physician-scientist serving veterans.
PUBLIC HEALTH RELEVANCE:
This proposal directly addresses the health needs of female veterans who increasingly contribute to the overall population of veterans in the US. Lupus is a devastating disease affecting young and middle-age women, particularly women of color, because they are more prone to immune disturbances. Normally, the immune system protects the body from bacteria and viruses. When it weakens, humans develop infections, allergies, and rheumatic diseases, particularly lupus. There is a type of white blood cell called a regulatory T lymphocyte, or "Treg"
for short, whose job is to help keep the immune system in balance. When Tregs are disturbed, the immune system can go out of control and start attacking one's own body, destroying joints, blood vessels, kidneys, heart, brain, and other organs. The purpose of this project is to better understand how and why Tregs are affected in veterans with lupus and to find new and better ways to make Tregs better and thus make veterans healthier.
描述(由申请人提供):
退伍军人中女性,特别是有色人种女性的比例正在增加。这部分退伍军人经常患上狼疮,这是一种毁灭性的全身性自身免疫性疾病。有必要了解狼疮的机制,并培养能够使用创新方法管理这种疾病的医生科学家。最近的研究结果表明,一类称为调节性T细胞(Tcells)的T淋巴细胞主要参与调节健康和疾病中的免疫系统,包括退伍军人。目前在人类中识别TcB的方法发展得很差,因为小鼠中这些细胞的标记物FoxP 3在人类中并不可靠。我们的研究表明,一个新的标记,太阳神,与FoxP 3相结合,可以可靠地识别人类Tendon。通过使用金标准测试将Helios阳性TCLs验证为定型TCLs,表明它们不产生免疫活化细胞因子并且还具有FoxP 3基因的完全去甲基化,与Helios阴性FoxP 3阳性细胞相反,Helios阴性FoxP 3阳性细胞产生细胞因子并且仅部分FoxP 3基因去甲基化。我们证明,在临床上更严重的系统性红斑狼疮患者中,Helios阳性FoxP 3细胞和Helios阴性FoxP 3阳性细胞之间的比率有降低的趋势。此外,我们还发现,在低至中度临床严重程度的狼疮患者中,Helios阳性THBG的增加与类固醇治疗直接相关。此外,我们观察到I型干扰素高的炎症环境抑制调节性T细胞。基于这些观察结果,我们假设使用Helios与FoxP 3组合用于鉴定TcB提供了一种更可靠的方法来评估免疫紊乱和对治疗的反应。我们还假设I型干扰素抑制Treg的扩增和激活,这可能被皮质类固醇逆转。在拟议的研究中,我们将通过解决以下具体目标来评估这些假设的有效性。在具体目标1中,我们将通过扩大我们在大量系统性红斑狼疮患者中的TcR研究,验证Helios与FoxP 3结合作为天然调节性T细胞的明确标志物。在具体目标2中,我们将断言I型干扰素以调节性T细胞为代价驱动效应T细胞的扩增。我们将确定I型干扰素抑制调节性T细胞的机制。在特定目标3中,将进行横断面分析以确定类固醇如何促进Treg扩增并可能逆转I型干扰素的负面作用。这项研究的目标是通过确定那些可以从专门针对刺激THBG的治疗中受益的狼疮患者来改善退伍军人,特别是女性退伍军人的福祉。通过研究I型干扰素抑制人TcB的机制和类固醇促进人TcB的途径,我们希望发现新的治疗靶点,不仅用于治疗狼疮,还用于治疗退伍军人中普遍存在的各种自身免疫性、过敏性和炎症性疾病。同时,这项工作将使候选人成为一名独立的医生-科学家,研究重点是免疫系统的调节,以最终改善患者的生活。培训和指导计划通过提出转化研究,生物统计学和生物伦理学课程的具体计划,概述了实现这一目标的途径。拟议的研究计划将使申请人在其主要导师Sergei Atamas博士的专业知识下接触分子生物学和受体信号传导方面的新研究技术。Violeta罗斯博士,第一位共同导师,将在SLE患者的护理和研究方面提供临床和研究专业知识。第二位共同导师Marc Hochberg博士将在转化研究和生物统计方法方面提供指导。此外,由T细胞生物学、FoxP 3表观遗传学、临床研究和初级研究人员培训方面的知名专家组成的咨询委员会将有助于确保申请人成功成为为退伍军人服务的独立医生-科学家。
公共卫生关系:
这项提案直接解决了女性退伍军人的健康需求,她们对美国退伍军人的总体人口贡献越来越大。狼疮是一种毁灭性的疾病,影响年轻和中年妇女,特别是有色人种的妇女,因为她们更容易出现免疫紊乱。通常,免疫系统保护身体免受细菌和病毒的侵害。当它减弱时,人类会发生感染,过敏和风湿性疾病,特别是狼疮。有一种白色血细胞称为调节性T淋巴细胞,或“Treg”。
简而言之,它的工作是帮助保持免疫系统的平衡。当甲状腺受到干扰时,免疫系统可能会失控并开始攻击自己的身体,破坏关节,血管,肾脏,心脏,大脑和其他器官。该项目的目的是更好地了解Tendon如何以及为什么会影响狼疮退伍军人,并找到新的更好的方法来使Tendon更好,从而使退伍军人更健康。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
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 }}
Amit Golding其他文献
Amit Golding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('Amit Golding', 18)}}的其他基金
Investigation of Regulatory T Cells in Veterans with Rheumatologic Disease
患有风湿病的退伍军人中调节性 T 细胞的研究
- 批准号:
8698396 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Investigation of Regulatory T Cells in Veterans with Rheumatologic Disease
患有风湿病的退伍军人中调节性 T 细胞的研究
- 批准号:
8499020 - 财政年份:2012
- 资助金额:
-- - 项目类别: