PhD Thesis Proposal Seminar

Presented by: Margaret Thomas Freeberg

K-207 Auditorium (2-6408), University of Rochester Medical Center

“Development of siRNA Therapeutics Targeting Serpine1 for Treatment of Tendon Adhesions”

Supervised by: Prof. Hani Awad

Flexor tendon injuries of the hand are prone to the formation of debilitating adhesions, which can significantly impact quality of life. Despite improvements in surgical techniques and rehabilitation, adhesion formation occurs in 30-60% of the hand injuries. Presently there are no pharmacological or biological agents for prevention of adhesion formation following tendon injury. The overall objective of this proposal is to develop small interfering RNA (siRNA) therapeutics to alter gene expression and dampen the excessive fibrosis leading to adhesion formation following tendon injury by promoting ECM remodeling without compromising strength. Tendon adhesions are associated with aberrant transforming growth factor-β1 (TGF-β1) signaling, which stimulates matrix synthesis and inhibits remodeling. Towards the identification of downstream signaling targets, we demonstrated that TGF-β1 significantly upregulates the protease-suppressor, plasminogen activator inhibitor 1 (PAI-1). Because of PAI-1’s role in the inhibition of the plasmin activation cascade, which is involved in ECM remodeling, and it’s association with fibrosis in a number of tissues, it is considered as a therapeutic target for the treatment of flexor tendon adhesion formation. Due to numerous challenges associated with the binding kinetics to inhibit PAI-1 using neutralizing antibodies and small molecule inhibitors, we propose to use injectable siRNA delivery as an effective strategy for localized inhibition of the gene encoding for PAI-1 in vivo. Our central hypothesis is that PAI-1 represents a therapeutic target, downstream of TGF-β, which when inhibited could enhance endogenous repair and reduce the fibrotic response without compromising mechanical properties. The rationale that underlies the proposed research is that the development of siRNA transfection strategies for local inhibition of Serpine1, the gene encoding PAI-1, to modulate the fibrosis pathway will lead to enhanced matrix remodeling independently of matrix deposition and significantly improve treatment options for those who suffer from tendon adhesions.