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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08AR063696-01
Application #
8424067
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Mao, Su-Yau
Project Start
2013-07-01
Project End
2018-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$131,440
Indirect Cost
$9,440
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115