The Lung as an Originating Site of Autoimmunity in Rheumatoid Arthritis

描述(申请人提供)：应聘者：Demoruelle博士是风湿病学部的一名医学讲师，她将80%的全职专业精力投入到研究项目中，调查肺部在类风湿性关节炎(RA)临床前发展中的作用。她还在国家犹太人健康中心(NJH)接受了10%的临床预约，并为教育和行政活动付出了10%的努力。到目前为止，她对这一研究领域的奉献从她的3本第一作者同行评议的出版物3中可见一斑。 第一作者回顾了文章发表，她是首席研究员的5个赠款基金奖，包括NIH贷款偿还奖，以及她在国内和国际科学会议上的多次演讲。根据她为这个奖项制定的职业发展计划，她 目前的职业目标是扩展她先前的研究，以确定肺是RA自身免疫的起始部位，因为这将作为未来独立研究努力的基础。她的其他近期职业目标包括将自己确立为临床前RA研究领域的领导者，并于2017年5月在科罗拉多大学丹佛大学完成临床调查博士学位。在她为这个K23奖项组织的专家指导团队的帮助下，以及她的其他现有指导团队(包括她的博士论文委员会和她的科学家发展奖指导委员会)的帮助下，她将获得帮助和指导，以成功地完成拟议的K23项目的目标。从这个项目中产生的新的研究技能、结果数据和导师将为她奠定基础，以便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。环境：Demoruelle博士得到了她所在部门和部门负责人的承诺，确保她有80%的受保护时间用于这份K23提案中详细说明的研究和职业发展活动。她可以从NIH资助的类风湿性关节炎病因学研究(血清)队列以及科罗拉多大学(CU)和NJH的诊所获得这一项目的招募对象。由于NJH是美国领先的呼吸内科和研究医院，她将有机会为这个项目和未来的项目招募患有肺部疾病的独特对象。在科罗拉多大学，她将得到位于科罗拉多州儿童医院的临床和翻译研究中心核心实验室(这是一个肺液处理中心)、科罗拉多大学丹佛微生物组研究联盟(人类微生物组研究的领先机构)和科罗拉多州生物统计联盟的全力支持。在CU，她将通过CU Denver临床科学研究生项目继续她的临床调查博士课程，预计2017年5月毕业。她的博士论文项目名为“肺作为RA自身免疫的起始部位”，这与她申请K23的建议项目是一致的。此外，Demoruelle博士将有机会进入CU更大的研究社区，包括部门、部门和大学范围的研究论坛，在那里她将能够展示她的研究并获得反馈，并参加与她的研究领域相关的各种最新进展的演讲。除了受保护的时间和财政支持外，Demoruelle博士目前还有一间办公室、装有文字处理和统计软件的计算机、电话、打印机、复印机/传真机和风湿科提供的秘书支持，这些支持将在整个职业发展奖的有效期内延续。研究：本项目的总体假设是，RA的自身免疫起源于肺，而RA在肺中的启动与肺中特定的细菌群落组成有关。这一假说是基于我们实验室先前的数据，表明循环中的RA相关自身抗体(Abs)和呼吸道炎症先于RA的关节炎症，并且利用诱导痰检测，在一些处于临床前RA时期的人的肺中似乎产生了RA相关的Abs。此外，我们实验室的初步数据表明，处于RA临床前发展阶段的受试者肺内RA相关抗体的纵向变化和肺部细菌组成的差异将为RA的病因提供新的见解。在这项K23提案中，我们在这些发现的基础上，同时使用在早期临床诊断的RA受试者、基于家族性或血清学生物标记物危险因素的未来RA风险受试者和健康对照中收集的痰和血清样本。在横断面中，我们将对痰和血清中与RA相关的抗体进行比较研究，假设抗体在痰中的分布比在RA患者和RA高危人群的血清中更高，这表明它们是在肺中产生的。在纵向研究中，我们将评估痰和血清中RA相关抗体的稳定性和演变，以进一步确定这些抗体的肺来源，并识别代表肺中RA相关自身免疫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样本来表征与肺中RA相关抗体相关的细菌(特定的分类群和更大的群落)，表明这些细菌可能参与了RA相关自身免疫的肺生成。

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.