Defining the relationship between attenuated insulin receptor signaling and fibrosis in diabetic tendinopathy



 DESCRIPTION (provided by applicant): This NIAMS K01 Mentored Research Scientist Development Award application outlines the career development plan and research training activities that will facilitate Dr. Alayna Loiselle's development in to a successful independent investigator in the field of diabetic tendinopathy. Drs. Hani Awad, Edward Schwarz and Robert Mooney will provide mentorship and training to enhance Dr. Loiselle's expertise in basic tendon biology and the impact of type II diabetes mellitus (T2DM) on tendon homeostasis and repair. Together we have created an integrated training plan that incorporates didactic training focused on tendon biology, T2DM and insulin receptor (IR) signaling, as well as professional development training in grantsmanship, and laboratory management; research training will include the use of cutting-edge imaging to assess collagen organization during disease progression, the use of complex mouse genetic models which will answer fundamental questions regarding the cell populations involved in flexor tendon (FT) homeostasis and repair, and the function of IR signaling in these processes. We have also established clear hallmarks of success for each training component. This program will be used to test the overall hypothesis that loss of IR signaling in FT cells results in suppressed matrix remodeling and increased fibrosis in diabetic tendons. This hypothesis is based on our preliminary data, which demonstrates suppressed IR signaling in T2DM tendons, concurrent with loss of FT gliding function and impairments in strength. These pathological tendon changes in the murine model of T2DM recapitulate the changes that are seen clinically as part of the `diabetic hand syndrome' in which FTs become fibrotic and are unable to smoothly glide through the synovial sheath. Impaired FT gliding impedes flexion of the fingers, which can compromise the function of the entire hand. In addition, diabetic tendons are more prone to rupture, which further complicates the already challenging repair of FTs; up to 40% of non-diabetic FT repairs heal with significant complications including the formation of adhesions between the tendon and synovial sheath, resulting in loss of gliding function. Healing is further impaired in diabetic patients, indicating the need to understand the cellular and molecular changes in both disrupted FT homeostasis and impaired healing in T2DM in order to identify novel therapeutic approaches to restore FT function in this rapidly expanding patient population. In the present study we will define the effects of T2DM on FT homeostasis and healing, and identify attenuated IR signaling as the primary mechanism of diabetic tendinopathy. We will also use ex-vivo and in vitro approaches to identify suppression of matrix metalloproteinase activity as a mechanism of impaired matrix remodeling and tendon fibrosis. This training program will provide Dr. Loiselle with intensive training in the effects of T2DM on tendon, but will also result in the generation of novel preliminary data, which will act as a platform for Dr. Loiselle's future research program focused on translational approaches to maintaining FT function and improving healing in the context of T2DM.