# NIH grant: Microbial Drivers and Pathogenic Mechanisms in Rheumatoid Arthritis Natural History (1P01AI194959-01) — retained record

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NIH grant 1P01AI194959-01: Microbial Drivers and Pathogenic Mechanisms in Rheumatoid Arthritis Natural History
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Jane Hoyt Buckner. Award: $2322266.
Start: 2026-07-01T00:00:00.
It is now known that the great majority of individuals who ultimately develop seropositive rheumatoid arthritis
(RA) pass through a multi-year pre-RA period characterized by the asymptomatic presence of RA-related
autoantibodies. In cross-sectional studies, subsets of pre-RA individuals have been shown to exhibit sites of
mucosal inflammation, including gut, lung and oral/periodontal, that are associated with bacterial dysbiosis,
and with murine models demonstrating likely pathogenic relevance of these findings. To understand the
longitudinal inter-relationships between the presence of site-specific mucosal inflammation and dysbiosis to the
development of systemic autoimmunity and ultimately clinical RA, a highly interactive group of investigators
across institutions have come together through this program project proposal, entitled “MOSAIC: Microbial
Drivers and Pathogenic Mechanisms in Rheumatoid Arthritis Natural History”. One of the most important
outcomes of the recent collaborative efforts of this group has been the demonstration that bacterial dysbiosis
and chronic inflammation at these specific mucosal sites appear to promote the initial development of the RA
disease-specific loss of tolerance to autoantigens. Thus, the central hypothesis of this proposal, upon which
the MOSAIC investigators will focus in a highly collaborative and synergistic manner, is that causal mucosal
bacterial strains initiate and promote the transition to clinical RA in at-risk individuals through the development
of distinct and definable immunologic drivers of autoimmunity. The MOSAIC Project and Core focus, activities,
synergies, and inter-relationships are described within this Overall section. Included within MOSAIC are three
Projects and two Cores. Project 1 will investigate how the specific causally associated mucosal bacterial
microbiota evolve over time in individual at-risk individuals who then develop RA. In parallel, Project 2 will
address the hypothesis that immune responses to mucosal microbiota promote molecular mimicry and epitope
spreading, resulting in autoimmunity to citrullinated autoantigens. In Project 3, classification and disease
development models will be built that enhance the understanding of how the identified specific bacterial
microbiota and citrullinated autoantigen responses interact to drive subsequent arthritis. Through these efforts,
Project 3 will also work to improve prediction for transitions from pre-RA to the development of clinical RA. To
support the Projects, two Cores will be utilized. The Administrative Core will organize synergistic study
activities across sites as well as manage the budget and publication strategies and interactions with
NIH/NIAID. In addition, the Population and Data Management Core will maintain cohorts and data generated
within MOSAIC. Dr. Michael Holers will serve as the Contact PI of MOSAIC and Director of the Administrative
Core. He will be joined by Drs. Kristi Kuhn and Jane Bucker as leaders of Project 1 and Project 2, respectively,
as well as constituting the Multiple PI team. Drs. Fan Zhang and Kevin Deane will lead Project 3 and the
Population and Data Management Core, respectively. Finally, an External Advisory Committee will be formed.
```



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