The Lung as an Originating Site of Autoimmunity in Rheumatoid Arthritis

肺是类风湿性关节炎自身免疫的起源部位

• 批准号: 8764655
• 负责人: M. Kristen Demoruelle
• 金额: $ 13.15万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8764655
• 关键词: Affect; Anatomic Sites; Antigens; Appointment; Area; Arthritis; Autoantibodies; Autoimmune Responses; Autoimmunity; Award; Bacteria; Biological Markers; Biometry; Center for Translational Science Activities; Clinic; Clinical; Clinical Research; Clinical Sciences; Clinical Trials; Colorado; Commit; Communities; Comparative Study; Computer software; Computers; DNA Sequence; Data; Dedications; Development; Development Plans; Diagnosis; Disease; Doctor of Philosophy; Doctor' s Degree; Education; Enrollment; Ensure; Environment; Etiology; Evaluation; Evolution; Feedback; Financial Support; Foundations; Funding; Future; Generations; Goals; Grant; Head; Health; Healthcare; Histologic; Hospitals; Human Microbiome; Immune; Immunoglobulin A; Immunologics; Incidence; Individual; Inflammatory; Institutes; Instruction; International; Joints; K-Series Research Career Programs; Laboratories; Lead; Liquid substance; Longitudinal Studies; Lung; Lung diseases; Medicine; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Morbidity - disease rate; Mucous Membrane; PRTN3 gene; Pathogenesis; Pattern; Pediatric Hospitals; Peer Review; Peptides; Play; Population; Prevalence; Prevention; Prevention strategy; Principal Investigator; Process; Publications; Recruitment Activity; Research; Research Project Grants; Resources; Rheumatoid Arthritis; Rheumatoid Factor; Rheumatology; Risk; Risk Factors; Role; Sampling; Scientist; Serological; Serum; Site; Sputum; Synovitis; Taxon; Telefacsimile; Telephone; Testing; Time; United States National Institutes of Health; Universities; Word Processing; Work; airway inflammation; arthropathies; base; career; career development; clinical risk; cohort; comparative; cost; cyclic citrullinated peptide; design; follower of religion Jewish; high risk; insight; instructor; meetings; microbiome; mortality; novel; pre-clinical; prevent; programs; public health relevance; research and development; respiratory; skills

DESCRIPTION (provided by applicant): Candidate: Dr. Demoruelle is an Instructor of Medicine in the Division of Rheumatology where she has 80% of her full-time professional effort committed to her research projects investigating the role of the lung in the pre- clinical period o rheumatoid arthritis (RA) development. She also has a 10% clinical appointment at National Jewish Health (NJH), and 10% effort for education and administrative activities. To date, her dedication to this field of research is evident by her 3 first-author peer-reviewed publications, 3 first-author review article publications, 5 grant funding awards for which she is the principal investigator including the NIH Loan Repayment Award, and her many presentations at national and international scientific meetings. In line with her career development plan for this award, her immediate career goals are to expand her prior studies to determine the lung is an originating site of autoimmunity in RA as this will serve as the foundation for future independent re- search endeavors. Her additional immediate career goals include establishing herself as a leader in the field of preclinical RA research and completing her doctoral degree in clinical investigation from the University of Colorado Denver in May 2017. With the assistance of her expert mentoring team that is organized for this K23 award, as well as her other established mentoring teams that include her PhD thesis committee and her Scientist Development Award mentoring committee, she will obtain the assistance and instruction to successfully complete the aims of the proposed K23 project. The new research skills, resultant data, and mentorship that arise from this project will lay the groundwork so that she can achieve her long term career goals to become an independent scientist in the field of preclinical RA research, and ultimately understand the mechanisms that initiate RA so that effective strategies targeting these mechanisms can be applied to prevent RA. Environment: Dr. Demoruelle has a commitment from her Department and Division heads that ensures her 80% protected time for the research and career development activities detailed in this K23 proposal. She has access to subjects for recruitment for this project from the novel NIH-funded Studies of the Etiology of RA (SERA) cohort as well as clinics at the University of Colorado (CU) and NJH. Because NJH is a leading US hospital for respiratory medicine and research, she will have access to recruit unique subjects with lung dis- ease for this project as well as future projects. At CU, she will have the full support of the Clinical and Translational Research Center Core Laboratory located at Children's Hospital Colorado that is a pulmonary fluid processing center, the CU Denver Microbiome Research Consortium that is a leading institute in studies of the human microbiome, and the Colorado Biostatistics Consortium. At CU, she will continue her doctoral studies in clinical investigation through the CU Denver graduate program in Clinical Science with an expected graduation date of May 2017. Her doctoral thesis project is entitled, "The Lung as an Initiating Site of Autoimmunity in RA," and it is in-line with the proposed project of her K23 application. Furthermore, Dr. Demoruelle will have access to the larger research community at CU including Divisional, Departmental, and University-wide research forums where she will be able to present her research and receive feedback, as well as attend a variety of presentations regarding state-of-the-art advances related to her research areas. In addition to protected time and financial support, Dr. Demoruelle currently has an office, computer with word processing and statistical software, telephone, printer, copy/fax machine and secretarial support provided by the Division of Rheumatology that will be extended throughout the duration of this career development award. Research: The overall hypothesis of this project is that autoimmunity in RA originates in the lung, and the initiation of RA in the lung is related to specific bacterial community compositions in the lung. This hypothesis is based on prior data from our lab demonstrating that circulating RA-related autoantibodies (Abs) and airways inflammation precede joint inflammation in RA, and utilizing induced sputum testing, RA-related Abs appear to be generated in the lung in some individuals who are in the preclinical RA period. In addition, preliminary data from our lab suggest that longitudinal changes in lung RA-related Abs and differences in lung bacterial compositions in subjects who are in the preclinical period of RA development will provide novel insight into the etiology of RA. In this K23 proposal, we build upon these findings and use simultaneously collected sputum and se- rum samples in subjects with early clinically-diagnosed RA, subjects at risk for future RA based on familial or serologic biomarker risk factors, and healthy controls. In cross-section, we will perform comparative studies of RA-related Abs in sputum and serum with the hypothesis that Abs will be more prevalent in the sputum than the serum in subjects with RA and subjects at risk for RA suggesting their generation in the lung. In longitudinal studies, we will evaluate the stability and evolution of RA-related Abs in the sputum and serum to further determine the lung origin of these Abs as well as to identify specific autoimmune responses that represent the earliest targets of RA-related autoimmunity in the lung. Finally, we will utilize the sputum samples from these subjects to characterize bacteria (specific taxa and larger communities) that are associated with RA-related Abs in the lung, suggesting these bacteria may be involved in the lung generation of RA-related autoimmunity.

描述（由申请人提供）：候选人：Dr. Demoruelle是风湿病学系的医学讲师，她将80%的全职专业精力投入到她的研究项目中，研究肺在类风湿性关节炎（RA）发展的临床前阶段的作用。她还在国家犹太健康（NJH）有10%的临床任命，10%的努力用于教育和行政活动。迄今为止，她对这一研究领域的奉献精神通过她的3篇第一作者同行评审出版物、3 第一作者评论文章出版物，5个赠款资助奖，她是主要研究者，包括NIH贷款偿还奖，以及她在国家和国际科学会议上的许多演讲。为了配合她的职业发展计划，她 近期的职业目标是扩展她先前的研究，以确定肺是类风湿关节炎自身免疫的起源部位，因为这将作为未来独立研究的基础。她的其他近期职业目标包括确立自己作为临床前RA研究领域的领导者，并于2017年5月完成科罗拉多丹佛大学临床研究博士学位。在她为K23奖组织的专家指导团队以及其他已建立的指导团队（包括博士论文委员会和科学家发展奖指导委员会）的帮助下，她将获得帮助和指导，以成功完成拟议的K23项目的目标。新的研究技能，由此产生的数据和指导，从这个项目将奠定基础，使她能够实现她的长期职业目标，成为临床前RA研究领域的独立科学家，并最终了解启动RA的机制，以便针对这些机制的有效策略可以应用于预防RA。工作环境：Demoruelle博士的部门和部门负责人承诺，确保她80%的时间用于本K23提案中详细说明的研究和职业发展活动。她可以从NIH资助的RA病因学研究（SERA）队列以及科罗拉多大学（CU）和NJH的诊所中招募受试者。由于NJH是美国领先的呼吸医学和研究医院，她将有机会为这个项目以及未来的项目招募独特的肺部疾病受试者。在CU，她将得到位于科罗拉多儿童医院的临床和转化研究中心核心实验室的全力支持，该实验室是肺液处理中心，CU丹佛微生物组研究联盟是人类微生物组研究的领先机构，以及科罗拉多生物统计学联盟。在CU，她将继续通过CU丹佛临床科学研究生课程进行临床研究的博士研究，预计毕业日期为2017年5月。她的博士论文项目题为“肺作为RA自身免疫的起始部位”，这与她的K23申请的拟议项目一致。Demoruelle将有机会在CU更大的研究社区，包括分区，部门和大学范围内的研究论坛，在那里她将能够展示她的研究和接收反馈，以及参加各种关于国家的介绍最先进的进展与她的研究领域。除了受保护的时间和财政支持外，Demoruelle博士目前还拥有一间办公室，配有文字处理和统计软件的计算机，电话，打印机，复印/传真机以及由流变学部门提供的秘书支持，这些支持将在整个职业发展奖期间延长。调研：本项目的总体假设是，RA的自身免疫起源于肺，并且肺中RA的起始与肺中特定的细菌群落组成有关。这一假设是基于我们实验室的先前数据，这些数据表明RA相关的循环自身抗体（Abs）和气道炎症先于RA的关节炎症，并且利用诱导痰检测，RA相关的Abs似乎在一些处于临床前RA期的个体的肺中产生。此外，我们实验室的初步数据表明，处于RA发展临床前阶段的受试者中肺RA相关Ab的纵向变化和肺细菌组成的差异将为RA的病因学提供新的见解。在本K23提案中，我们以这些发现为基础，在早期临床诊断的RA受试者、基于家族或血清学生物标志物风险因素存在未来RA风险的受试者和健康对照者中同时采集痰液和血清样本。在横断面研究中，我们将对痰液和血清中的RA相关Ab进行比较研究，假设在RA受试者和有RA风险的受试者中，痰液中的Ab比血清中的Ab更普遍，表明其在肺中产生。在纵向研究中，我们将评估痰液和血清中RA相关Ab的稳定性和演变，以进一步确定这些Ab的肺部来源，并确定代表肺部RA相关自身免疫的最早靶点的特异性自身免疫反应。最后，我们将利用这些受试者的痰液样本来表征与肺中RA相关Ab相关的细菌（特定分类群和更大的群落），表明这些细菌可能参与肺产生RA相关自身免疫。