Our primary objective is to identify novel and effective approaches to the prevention andtreatment of Graves' ophthalmopathy (GO), the ocular disease linked to Graves'hyperthyroidism. Histopathologic changes within the GO orbit are striking and includeaccumulation of hyaluronic acid (HA) and edema, increased numbers of mature fat cells, andthe presence of inflammatory cytokines and chemokines. The resultant tissue remodeling, onceestablished, can at best be imperfectly reversed or modulated through surgical intervention oraggressive immunotherapy. Our studies of the pathogenesis and clinical expressions of GO overthe past two decades have led to new insights into the cellular and molecular mechanismsunderlying the ocular tissue changes seen in the disease. Our laboratory has recentlyestablished a role for thyrotropin receptor (TSHR) autoantibodies in the initiation of thesechanges. We are now poised to greatly increase the significance and impact of this work. Thecentral hypotheses to be tested are that autoantibodies directed against the TSHR in GO orbitalfibroblasts initiate and sustain the disease processes in these cells and that small-moleculeligand antagonists of this receptor can inhibit these effects. In addition, we suggest thatpatients at high risk for the development or progression of GO can be identified using novelbiomarkers and by prospective study of hyperthyroid patients using currently obtainableclinical data. In this application, we will expand our studies concerning mechanisms involvedin TSHR activation by stimulatory, neutral and blocking autoantibodies in GO (Aim 1). Inaddition, we will determine the ability of drug-like small molecule ligand antagonists of TSHRto block receptor activation, HA synthesis and adipogenesis in orbital fibroblasts. These studieswill clarify the potential utility of these compounds as novel therapy.
In Aim 2, we will identifynew biomarkers of disease activity that might in future be used to identify high-risk patients.
In Aim 3, we will develop a clinical prediction tool to identify at-risk patients in a prospectivestudy using currently available patient data. The ability to reliably identify patients at high riskfor GO onset or progression would have significant impact on the disease as these patientswould benefit most from novel therapies aimed at preventing the tissue remodelingcharacteristic of established disease.PHS 398/2590 (Rev. 06/09) Page Continuation Format Page
The goal of our research is to find new and effective ways to prevent or treat Graves'ophthalmopathy (GO), the eye condition linked to Graves'hyperthyroidism. Patients with GO can experience eye pain and swelling, visual problems including blindness, and disfiguring forward protrusion of the globes. Our studies using orbital cells and blood from these patients will clarify how the eye changes occur, find ways to block their development, and identify those patients with hyperthyroidism who are at greatest risk for GO development. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page
