Immunopathogenesis of Sjogren syndrome

干燥综合征的免疫发病机制

• 批准号: 8279735
• 负责人: Scott Matthew Lieberman
• 金额: $ 13.82万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8279735
• 关键词: Address; Adoptive Transfer; Advisory Committees; Affect; American; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Back; Bioluminescence; Bone Marrow; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Cervical lymph node group; Childhood; Chimera organism; Clinical; Data; Defect; Dental; Development; Diagnostic; Disease; Dryness; Early identification; Etiology; Event; Exocrine Glands; Faculty; Fellowship; Female; Functional disorder; Future; Gland; Goals; Homeostasis; Human; Image; Immune; Immune Tolerance; Immune system; In Vitro; Inbred NOD Mice; Individual; Inflammation; Inflammatory; Inflammatory Infiltrate; International; Lacrimal gland structure; Lymphocyte; Lymphocyte Biology; Lymphocytic Infiltrate; Mediating; Medical; Medicine; Mentors; Modality; Modeling; Mus; Non obese; Oral; Organ; Pathogenesis; Pediatric Hospitals; Pediatrics; Pennsylvania; Philadelphia; Population; Postdoctoral Fellow; Production; Program Development; Regulatory T-Lymphocyte; Reporter; Research; Research Personnel; Residencies; Rheumatism; Rheumatology; Role; Saliva; Salivary Gland Diseases; Salivary Glands; Scientist; Sialadenitis; Site; Sjogren' s Syndrome; Students; Symptoms; Syndrome; T-Cell Development; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Therapeutic; Time; Training; Training Programs; Universities; Vision; Wood material; Xerostomia; authority; autoimmune exocrinopathy; autoimmune rheumatologic disease; base; career; congenic; cytokine; diabetic; experience; eye dryness; in vivo; insight; lymph nodes; male; member; mouse model; prevent; professor; research study; sex; sexual dimorphism; skills; tool

DESCRIPTION (provided by applicant): This proposal describes a 5-year training program for the development of an academic career in Pediatric Rheumatology. The PI has completed formal residency and fellowship training in Pediatrics and Pediatric Rheumatology at The Children's Hospital of Philadelphia and is currently expanding his scientific skills in immune tolerance and autoimmunity models. Dr. Gary Koretzky, an international authority in lymphocyte biology, will mentor the PI's scientific development. Dr. Koretzky is Vice Chair for Research, Chief Scientific Officer, and Francis C. Wood Professor of Medicine at the University of Pennsylvania. He has extensive experience in successfully mentoring students, post-doctoral fellows, and junior faculty members. To further promote the investigator's scientific development, an Advisory Committee comprising highly regarded medical scientists including Drs. Steven Reiner, Terri Finkel, and Edward Behrens has been established. Sj¿gren syndrome experts Drs. Seunghee Cha and Eduardo M. Rocha will participate in advisory roles as well. Drs. Finkel and Behrens are also leaders in Pediatric Rheumatology and will mentor the PI's clinical development. The proposed research focuses on mechanisms of immune dysregulation in the development of Sj¿gren syndrome, a common but poorly understood autoimmune disease. Sj¿gren syndrome is caused by destruction and dysfunction of lacrimal and salivary glands with subsequent profound ocular and oral dryness which may progress to sight-threatening or severe dental manifestations. The nonobese diabetic (NOD) mouse spontaneously develops autoimmunity resembling Sj¿gren syndrome, providing a tool for studying disease initiation. Inflammatory cell infiltrates of lacrimal and salivary glands are dominated by T cells, but the contributions of different T cell subsets in disease initiation are unknown. Regulatory T cells, a subset of CD4+ T cells which prevent autoimmunity in normal hosts, are organized anatomically in non-autoimmune-prone mice; however, whether this is disrupted in autoimmune-prone mice is unknown. Female NOD mice develop salivary gland inflammation, whereas males develop lacrimal gland disease. Whether this is due to immune- cell intrinsic or extrinsic mechanisms is unknown. This proposal specifically aims to: 1) define the roles of CD8+ and CD4+ T cells in disease initiation; 2) define the extent and mechanisms of regulatory T cell defects in the NOD model of Sj¿gren syndrome. Understanding the earliest events in the development of Sj¿gren syndrome autoimmunity will provide targets for better diagnostic and therapeutic modalities for use in this and other autoimmune diseases. PUBLIC HEALTH RELEVANCE: Sj¿gren syndrome is an autoimmune disease characterized by destruction of tear and saliva producing glands resulting in profound dry eye and dry mouth which may result in sight-threatening or severe dental complications. Despite being one of the most common autoimmune rheumatologic diseases, affecting up to 4 million Americans, the cause of Sj¿gren syndrome is unknown. This proposal is aimed at identifying the components of the immune system which are responsible for the initiation of inflammation of lacrimal and salivary glands, which will provide targets for better diagnostic and therapeutic modalities for use in this and other autoimmune diseases.

描述（由申请人提供）：该提案描述了一个为期 5 年的小儿风湿病学术职业发展培训计划。该 PI 已在费城儿童医院完成了儿科和儿科风湿病学的正式住院医师和进修培训，目前正在扩展其在免疫耐受和自身免疫模型方面的科学技能。淋巴细胞生物学领域的国际权威 Gary Koretzky 博士将指导 PI 的科学发展。 Koretzky 博士是宾夕法尼亚大学研究副主席、首席科学官和 Francis C. Wood 医学教授。他在成功指导学生、博士后研究员和初级教师方面拥有丰富的经验。为了进一步促进研究者的科学发展，咨询委员会由包括 Drs. 在内的备受尊敬的医学科学家组成。 Steven Reiner、Terri Finkel 和 Edward Behrens 已成立。干燥综合征专家 Drs. Seunghee Cha 和 Eduardo M. Rocha 也将担任顾问职务。博士。 Finkel 和 Behrens 也是儿科风湿病学领域的领导者，并将指导 PI 的临床开发。 拟议的研究重点是干燥综合征（一种常见但知之甚少的自身免疫性疾病）发展过程中免疫失调的机制。干燥综合征是由泪腺和唾液腺破坏和功能障碍引起的，随后会出现严重的眼部和口腔干燥，可能会发展为威胁视力或严重的牙齿表现。非肥胖糖尿病（NOD）小鼠自发产生类似于干燥综合征的自身免疫，为研究疾病的发生提供了工具。泪腺和唾液腺的炎症细胞浸润以 T 细胞为主，但不同 T 细胞亚群在疾病发生中的贡献尚不清楚。调节性 T 细胞是 CD4+ T 细胞的一个子集，可防止正常宿主的自身免疫，在非自身免疫倾向的小鼠中按解剖学组织。然而，在易患自身免疫的小鼠中，这种现象是否会被破坏尚不清楚。雌性 NOD 小鼠会出现唾液腺炎症，而雄性则会出现泪腺疾病。这是否是由于免疫细胞内在或外在机制所致尚不清楚。该提案的具体目的是：1）定义CD8+和CD4+T细胞在疾病发生中的作用； 2) 定义干燥综合征 NOD 模型中调节性 T 细胞缺陷的程度和机制。了解干燥综合征自身免疫发展的最早事件将为更好地诊断和治疗该疾病和其他自身免疫性疾病提供目标。 公众健康相关性：干燥综合征是一种自身免疫性疾病，其特征是泪液和唾液腺被破坏，导致严重干眼和口干，可能导致危及视力或严重的牙科并发症。尽管干燥综合征是最常见的自身免疫性风湿病之一，影响着多达 400 万美国人，但干燥综合征的病因尚不清楚。该提案旨在确定免疫系统中负责引发泪腺和唾液腺炎症的组成部分，这将为更好地诊断和治疗这种疾病和其他自身免疫性疾病提供目标。