Immunopathogenesis of Sjogren syndrome

干燥综合征的免疫发病机制

基本信息

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
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/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&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（由应用程序提供）：该提案描述了一项为期5年的培训计划，以开发儿科风湿病学学术职业。 PI已在费城儿童医院完成了儿科和小儿风湿病学的正式住所和奖学金培训，目前正在扩大他在免疫耐受性和自身免疫模型方面的科学技能。淋巴细胞生物学国际权威加里·科雷茨基（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，首席科学官和弗朗西斯·C·伍德医学教授。他在成功的心理学生，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，一个咨询委员会完成了包括DRS在内的高度考虑的医学科学家。史蒂文·雷纳（Steven Reiner），特里·芬克尔（Terri Finkel）和爱德华·贝伦斯（Edward Behrens）已建立。 SJ¿Gren综合征专家Drs。 Seunghee Cha和Eduardo M. Rocha也将参加咨询角色。博士。 Finkel和Behrens也是小儿风湿病学领导者，并将指导PI的临床发展。拟议的研究重点是免疫失调的机制在SJ¿Gren综合征的发展中，这是一种常见但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的破坏和功能障碍引起的，随后具有深刻的眼部和口腔干燥，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）小鼠赞助发展自身免疫，类似于SJ¿Gren综合征，提供了研究疾病倡议的工具。泪液和唾液网格的炎症细胞浸润主要由T细胞支配，但是不同T细胞亚群在疾病倡议中的贡献尚不清楚。调节性T细胞是预防正常宿主自身免疫性的CD4+ T细胞的子集，在非自动免疫性易免疫的小鼠中被解剖；但是，尚不清楚在自身免疫性的小鼠中是否会破坏这种情况。雌性点头小鼠会出现唾液聚糖炎症，而雄性患有泪腺疾病。这是由于免疫细胞固有或外在机制引起的。该提案特别旨在：1）定义CD8+和CD4+ T细胞在疾病倡议中的作用； 2）定义了SJ¿Gren综合征的NOD模型中调节T细胞缺陷的程度和机制。了解SJ�Gren综合征自动免疫发展中最早的事件将为更好的诊断和治疗方式提供目标，以便在这种和其他自身免疫性疾病中使用。