Immunopathogenesis of Sjogren syndrome

干燥综合征的免疫发病机制

基本信息

批准号：
8502508
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
项目类别：
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/8502508
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&apos 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

项目摘要

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）：该提案描述了一个为期 5 年的儿科风湿病学学术职业发展培训计划。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。他在免疫耐受和自身免疫模型方面的科学技能将指导 PI 博士的科学发展，Gary Koretzky 博士是淋巴细胞生物学领域的国际权威。宾夕法尼亚大学研究副主席、首席科学官兼 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员方面拥有丰富的经验，以进一步促进研究者的科学发展。成立了一个由备受尊敬的医学科学家组成的咨询委员会，其中包括 Steven Reiner 博士、Terri Finkel 博士和 Edward Behrens 博士。格伦综合征专家 Seunghee Cha 博士和 Eduardo M. Rocha 博士也将担任儿科风湿病学领域的领导者，并指导 PI 的临床开发。 Sj¿ 的发展格伦综合征，一种常见但人们知之甚少的自身免疫性疾病。格伦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牙齿的严重表现，非肥胖糖尿病（NOD）小鼠会自发产生类似于 Sj¿ gren 综合征，为研究疾病发生提供了一种工具。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（CD4+ T 细胞的一个亚群）在疾病发生中的作用尚不清楚。在正常宿主中预防自身免疫，在非自身免疫倾向的小鼠中在解剖学上是组织的；然而，在自身免疫倾向的小鼠中，这种结构是否被破坏尚不清楚。炎症，而男性则发生泪腺疾病。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）确定 CD8+ 和 CD4+ T 细胞在疾病发生中的作用；2）确定疾病发生的程度。 Sj¿ NOD 模型中调节性 T 细胞缺陷的机制了解 Sj¿ 发展中的最早事件。格伦综合征自身免疫将为更好的诊断和治疗方式提供目标，用于该疾病和其他自身免疫性疾病。