This K08 Mentored Clinical Scientist application provides a comprehensive plan to develop the scientific expertise, professional skills, and collaborations the applicant will need to transition to an independent academic research career. The research proposal examines a newly identified interaction between the cell adhesion molecule cadherin-11 (cad11) and receptor tyrosine kinase (RTK) platelet-derived growth factor receptors (PDGFRs) on rheumatoid arthritis (RA) synovial fibroblasts. During RA, marked activation and hyperplasia of synovial fibroblasts contributes to all aspects of RA disease pathogenesis, although the mechanisms responsible for fibroblast hyperplasia are poorly understood. The sponsor's laboratory previously identified cad11 as a specific marker and regulator of synovial fibroblast function in inflammatory arthritis. Since interactions between cadherins and RTKs like PDGFRs influence cell proliferation and differentiation in tumor and other tissue models, the applicant hypothesized that interactions between cad11 and PDGFRs may be important to regulate synovial fibroblast proliferation and survival in RA. This proposal develops three distinct aims to better understand the biology of this interaction and its role in inflammatory arthritis.
Aim 1 employs in vitro studies using human RA synovial fibroblasts to define the signaling pathways downstream of cad11 and PDGFR that promote synovial fibroblast proliferation and survival.
Aim 2 uses both biochemical and immunofluorescence approaches to understand the nature of the physical association between these two molecules and to determine its effect on PDGFR stability and signaling intensity.
Aim 3 demonstrates the relevance of cad11 PDGFR interactions to synovitis development by using a mouse inflammatory arthritis model to examine the effect of loss of cad11 expression on fibroblast proliferation, survival, and PDGFR expression in vivo. This proposal is core to the longer- range research goals of the applicant to better understand the mechanisms important for fibroblast accumulation and activation in RA, with the hope that identifying fibroblast-specific therapeutic targets that may provide more effective treatments for RA patients. To complement the research proposal, the applicant presents a training plan that details specific coursework to increase her scientific expertise and promote her professional development. She has chosen a mentor with a long-track record of developing physician scientists and has established a network of independent investigators to provide both scientific and career advice. In combination, the training and research plans outlined in this proposal provide a comprehensive platform to support the applicant's development into an independently-funded, academic researcher in rheumatology-focused basic and translational research.
Rheumatoid arthritis (RA) is a destructive autoimmune disease of the joints affecting 0.5-1% of the US population. Critical to RA development is activation of the fibroblast cells resident inside the joint, which amplify inflammation and drive cartilage and bone erosion. Understanding the pathways that promote activation and accumulation joint fibroblasts may provide new therapeutic targets to prevent long-term joint destruction in RA.
|Mizoguchi, Fumitaka; Slowikowski, Kamil; Wei, Kevin et al. (2018) Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis. Nat Commun 9:789|
|Nguyen, Hung N; Noss, Erika H; Mizoguchi, Fumitaka et al. (2017) Autocrine Loop Involving IL-6 Family Member LIF, LIF Receptor, and STAT4 Drives Sustained Fibroblast Production of Inflammatory Mediators. Immunity 46:220-232|
|Noss, Erika H; Watts, Gerald F M; Zocco, Davide et al. (2015) Evidence for cadherin-11 cleavage in the synovium and partial characterization of its mechanism. Arthritis Res Ther 17:126|
|Noss, Erika H; Nguyen, Hung N; Chang, Sook Kyung et al. (2015) Genetic polymorphism directs IL-6 expression in fibroblasts but not selected other cell types. Proc Natl Acad Sci U S A 112:14948-53|