Immunopathogenesis of Sjogren syndrome

干燥综合征的免疫发病机制

• 批准号: 8680239
• 负责人: Scott Matthew Lieberman
• 金额: $ 13.82万
• 依托单位: UNIVERSITY OF IOWA
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8680239
• 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.

描述（由申请人提供）：本提案描述了一个为期5年的培训计划，在儿科流变学的学术生涯的发展。PI已在费城儿童医院完成了儿科和儿科流变学的正式住院医师和奖学金培训，目前正在扩大他在免疫耐受和自身免疫模型方面的科学技能。加里·科雷茨基博士是淋巴细胞生物学的国际权威，他将指导PI的科学发展。Koretzky博士是研究副主席，首席科学官，和弗朗西斯C。宾西法尼亚大学的伍德医学教授。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，成立了一个咨询委员会，由包括Steven Reiner博士、Terri Finkel博士和Edward Behrens博士在内的备受推崇的医学科学家组成。干燥综合征专家Seunghee Cha和Eduardo M.罗查也将担任顾问。Finkel和Behrens博士也是儿科流变学的领导者，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）发展中的免疫失调机制。Sj？格伦综合征是由泪腺和唾液腺的破坏和功能障碍引起的，随后是严重的眼干燥和口腔干燥，这可能发展为威胁视力或严重的牙齿表现。非肥胖型糖尿病（NOD）小鼠自发产生类似干燥综合征的自身免疫，为研究疾病的发生提供了工具。泪腺和唾液腺的炎性细胞浸润以T细胞为主，但不同T细胞亚群在疾病发生中的作用尚不清楚。调节性T细胞是CD 4 + T细胞的一个亚群，可以防止正常宿主的自身免疫，在非自身免疫易感小鼠中组织解剖学上;然而，这是否在自身免疫易感小鼠中被破坏尚不清楚。雌性NOD小鼠发生唾液腺炎症，而雄性发生泪腺疾病。这是由于免疫细胞的内在或外在机制尚不清楚.该提案的具体目标是：1）确定CD 8+和CD 4 + T细胞在疾病起始中的作用; 2）确定Sj？gren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期事件将为更好地诊断和治疗这种和其他自身免疫性疾病提供目标。