Thursday, May 1, 2025
5/1/2025
Activation of Synovial Lining Fibroblasts in Rheumatoid Arthritis - PROJECT SUMMARY / ABSTRACT This proposal comprises a five-year research and career development program for Melanie H. Smith, MD, PhD to achieve independence as an investigator at the intersection of immunology and stromal biology in the human synovium. Dr. Smith is an Assistant Attending Physician in the Division of Rheumatology at Hospital for Special Surgery (HSS) and an Assistant Attending Professor of Medicine at Weill Cornell Medical College in New York City. She will conduct research under the joint mentorship of Dr. Laura Donlin (HSS) and Dr. Alexander Rudensky (Memorial Sloan Kettering Cancer Center) focused on understanding the role of synovial fibroblasts in rheumatoid arthritis (RA). Dr. Smith will engage in career development activities including didactics, workshops in grant writing and leadership, conferences, and acquisition of technical skills and scientific expertise. These activities will be augmented through regular input from her scientific advisory team. This training grant will generate key skills, data, and publications necessary to become an R01-funded independent investigator. Synovial fibroblasts (FLS) are the most abundant resident cells in the synovium and are implicated in multiple aspects of RA pathogenesis. FLS specifically within the synovial lining layer exhibit evidence of extensive activation and are selectively defined by accessibility of AP-1 transcription factor motifs. Here we will test the contributions of toll like receptor (TLR) ligands from the synovial fluid, and local expression of epidermal growth factor receptor (EGFR) ligands in activating AP-1 in FLS. The central hypothesis is that these activators of AP- 1, which are present in the synovial lining microenvironment, prime lining FLS to mount heightened responses to cytokines derived from infiltrating leukocytes, and that AP-1 driven gene expression drives FLS functional specialization. We will use primary human synovial fibroblasts both in culture and directly isolated from synovial tissue along with selective agonists, targeted inhibitors and CRISPR interference to interrogate the mechanistic basis and functional consequences of the FLS activation observed specifically in lining FLS. The significance of this proposal lies in the identification of key factors responsible for FLS activation that may further the development of FLS-targeted therapies in RA. This proposal is innovative in the investigation of non-cytokine driven priming in the establishment of inflammatory memory and the identification of the specific transcription factors involved using advanced sequencing methods as well as CRISPR in primary human FLS. Long-term, Dr. Smith aims to apply the expertise gained in this proposal to identify environmental and inflammatory signals that maintain and regulate synovial inflammation to improve treatment of RA.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).