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.

Public Health Relevance

Rheumatoid arthritis (RA) affects approximately 1% of the population leading to significant morbidity and increased mortality, and over $30 billion in annual health-care related costs in the USA alone. The findings from this project will explore the lung as an originating site of autoimmunity in RA, as well as characterize lung bacterial associations that may be mechanisms by which this process occurs. While we realize that this project is correlative, these findings can change the current paradigm of our understanding of the pathogenesis of RA. After these relationships have been explored, they will provide a strong foundation for additional mechanistic studies of RA development that will move us closer to understanding the pathogenesis of RA as well as designing effective prevention strategies for this disease. Specifically, identifying the lung as a site where RA originates, as well as identifying specific bacterial communities that directly influence the initiation of RA in the lung can lead to future therapies that are directed at specific mechanisms of RA development at the site of initiation (e.g. the lung), and these therapies could be utilized for novel treatments and/r prevention of RA. This project will also serve as an outstanding program for Dr. Demoruelle's independent career development. The project will establish key findings to support future independent projects in which she will evaluate specific immunologic mechanisms that generate RA-related autoimmunity in the lung, identify mechanisms by which RA-related autoantibodies can be initially generated in the lung and later transition to the joints, and explore other mucosa sites that may also be involved in the etiology of RA.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Mentored Patient-Oriented Research Career Development Award (K23)
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Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
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Mao, Su-Yau
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University of Colorado Denver
Internal Medicine/Medicine
Schools of Medicine
United States
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Demoruelle, M Kristen; Bowers, Emily; Lahey, Lauren J et al. (2018) Antibody Responses to Citrullinated and Noncitrullinated Antigens in the Sputum of Subjects With Rheumatoid Arthritis and Subjects at Risk for Development of Rheumatoid Arthritis. Arthritis Rheumatol 70:516-527
Demoruelle, M Kristen; Harrall, Kylie K; Ho, Linh et al. (2017) Anti-Citrullinated Protein Antibodies Are Associated With Neutrophil Extracellular Traps in the Sputum in Relatives of Rheumatoid Arthritis Patients. Arthritis Rheumatol 69:1165-1175
Hughes-Austin, Jan M; Gan, Ryan W; Deane, Kevin D et al. (2017) Association of Antibodies to Citrullinated Protein Antigens with Blood Pressure in First-Degree Relatives of Rheumatoid Arthritis Patients: The Studies of the Etiology of Rheumatoid Arthritis. Am J Nephrol 46:481-487
Deane, Kevin D; Demoruelle, M Kristen; Kelmenson, Lindsay B et al. (2017) Genetic and environmental risk factors for rheumatoid arthritis. Best Pract Res Clin Rheumatol 31:3-18
Gan, Ryan W; Bemis, Elizabeth A; Demoruelle, M Kristen et al. (2017) The association between omega-3 fatty acid biomarkers and inflammatory arthritis in an anti-citrullinated protein antibody positive population. Rheumatology (Oxford) 56:2229-2236