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Principal Investigator: Benjamin L Miller
Organization: UNIVERSITY OF ROCHESTER
Fiscal Year: 2023
Award: $387,521
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
Abstract
The field of Osteoimmunology was established in 2005 to understand how bone influences immune and
hematopoietic cells, as well as how hematopoietic and immune cells influence bone, in clinical conditions like
osteomyelitis. However, several critical research tools and rigorously validated protocols required to translate
discoveries into clinical diagnostics and interventions for osteomyelitis did not exist at the commencement of
this P50 Center of Research Translation on the Osteoimmunology of Bone Infection (CoRTOBI) 5 years ago.
Thus, we assembled a multidisciplinary team of investigators with extensive experience in bone pathology,
microbial pathogenesis, immunology, electron microscopy, biophysics, material science & engineering,
infectious disease and orthopaedic surgery, to enable several breakthroughs in the field that serve as the
scientific premise of this renewal application. Despite these major advances, additional assay and technology
development is needed to complete the long-term goals of CoRTOBI. Thus, the renewal goals of the
Osteoimmunology Research Core are to: 1) provide the CoRTOBI investigators with state-of-the-art bone
infection research resources that do not exist elsewhere; and 2) develop novel technologies and assays for
future osteoimmunology research on bone infection. Our approaches to achieve these goals are embodied by
the following Specific Aims. In Aim 1 we will process the samples and perform all of the electron microscopy
(EM) on the infected bone and fabricated nanoporous membranes in Project 1, the mRNA vaccine studies in
Project 2, and external collaborations, using EM methods published during the prior funding period. In Aim 2.1
we will fabricate all of the µSiM-CA devices needed for novel antibiotic drug screening. In Aim 2.2 we will
develop and validate novel µSiM-OLCN devices to assess haptotaxis and durotaxis behaviors of S. aureus in
vitro to elucidate the mechanism of S. aureus invasion and colonization of the OLCN of cortical bone during
chronic osteomyelitis, and in Aim 2.3 the Core will develop surface coatings on the µSiM-CA and µSiM-OLCN
chips to enable hypothesis testing of S. aureus adhesion and rigidity during asymmetric binary fission. In Aim
3.1 we will perform all of Luminex-multiplex assays for immune proteome and cytokine analyses, and In Aim
3.2 we will translate this experimental assay for research into a same-day, high throughput clinical diagnostic
called StaphAIR based on Arrayed Imaging Reflectometry technology that allows for the automated
measurement of anti-S. aureus antibodies in near-real time. The Osteoimmunology Core will also facilitate
emerging technologies and research in the Pilot and Feasibility Project Program (i.e. intravital microscopy to
quantify “the race for the surface” during S. aureus colonization of bone implants; automated tape-collecting
ultra-microtome (ATUMtome)/SEM methods for 3D imaging of infected OLCN; and an extension of StaphAIR).
Importantly, it is also our intent to share our resources with investigators outside of this CoRTOBI, and
transport our research platforms to other institutions with a research focus on bone infections.
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