Grant Application
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Prior Funding
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"TNFa confers pathogenic memory to RA FLS by inducing
Principal Investigator: Dr. George Kalliolias
Institution: Hospital for Special Surgery

Rheumatoid arthritis (RA) is a common disabling disease with increased mortality
and significant societal cost burden. Despite the introduction of novel biologic
drugs most patients never experience sustained remission of their symptoms.
Thus, the introduction of a novel therapeutic paradigm is a pressing necessity.
Our proposed project aims to characterize molecular targets in synovial
fibroblasts (FLS) with therapeutic potential. The role of FLS is critical in RA
pathogenesis, but research on FLS is limited and underfunded. The chronic
unremitting character of RA is a puzzling issue for scientists and clinicians. We
propose a novel concept to explain the perpetuation of RA inflammation: the
joint inflammatory milieu "primes" the chromatin landscape of FLS, allowing
unopposed and continuous transcription of pathogenic genes that fuel arthritis.

Our specific aims are:
1) to identify whether the inflammation-induced memory is transient and
reversible or permanent and irreversible
2) to identify the molecular mechanism that drives pathogenic memory in RA

We will address these questions with a series of experiments using primary
human FLS derived from RA patients and will investigate whether therapeutic
manipulation of FLS chromatin will abrogate "pathogenic memory".

The above project description is supplied by the Principal Investigator