Objective
The purpose of this proposal is to determine how inflammatory signals engineer remodeling of the beta-cell surface as an early step in the development of T1D.
Background Rationale
Type 1 Diabetes (T1D) is an autoimmune disease that leads to near complete ablation of the pancreatic beta-cell population. Recent clinical trials and FDA approval of the immunotherapy, teplizumab, demonstrate that immunosuppression can delay disease onset in high-risk patients, however individual responses are variable and limited in duration (mean delay of clinical onset is 32.5 months). While these results are encouraging, there remains an urgent need to improve disease detection for early intervention and better therapies for disease prevention. A major hurdle in identifying disease modifying therapies is a limited understanding of the beta-cell’s role in disease progression. Our study seeks to advance the understanding of early beta-cell defects that contribute to T1D progression. Our work has uncovered fundamental changes in the Golgi apparatus, a key organelle inside the beta-cell that sorts and packages beta-cell surface proteins. We propose that dysregulation of the Golgi acts as a molecular switch for generating immunogenic signals on the beta-cell surface. Remodeling the beta-cell surface may re-define how the beta-cell is perceived by immune effectors and thereby directly contribute to T1D development.
Description of Project
Type 1 diabetes (T1D) results from autoimmune destruction of the insulin-producing beta-cells. While insulin therapies can successfully manage the symptoms of T1D, insulin does not prevent or cure this devastating disease. Emerging evidence highlights the beta-cell as an active participant in disease progression, yet how the beta-cell contributes to its own demise remains a critical gap in the field. Our recent studies have uncovered a novel role for immune-derived inflammatory signals in remodeling the beta-cell’s surface that may provide critical insight into the beta-cell’s role in T1D development. We propose that inflammatory mediators activate a molecular switch in the beta-cell that generates immunogenic signals on the beta-cell surface. Our work will define the molecular mechanisms of how inflammatory signals activate this molecular switch and define key changes to the beta-cell surface.
Anticipated Outcome
Using biochemical, molecular, and histological techniques, our studies will define the molecular mechanisms of how immuno-modulation of beta-cell functions lead to remodeling the beta-cell surface. Our studies will define critical changes in beta-cell Golgi functions that coincide with islet inflammation during the presymptomatic phases of T1D. Furthermore, our studies will establish the molecular pathways used by inflammatory signals to modulate Golgi functions leading to immunogenic signals. Last, our studies will identify critical changes to beta-cell surface protein expression and modification by inflammatory signals that could serve as early signals for immune cell activation.
Relevance to T1D
Compelling evidence highlights a critical role for islet beta-cell dysfunction in the development of immunogenic signals that drive the transition from autoantibody positivity to the clinical onset of T1D. The cellular mechanisms that generate beta-cell neoantigens are not well understood, yet could have considerable therapeutic value for early intervention and possibly, disease prevention. Our study will reveal novel molecular mechanisms detailing how immuno-modulation of normal beta-cell functions leads to the adaptive remodeling of the beta-cell surface. Our studies will identify cell surface biomarkers that function either as distress signals of beta-cell damage or possibly camouflage as beta-cells attempt to evade immunodetection and destruction. Thus, our work may lead to the discovery of novel biomarkers for T1D progression and identification of pathways for novel therapeutic approaches to suppress autoimmunity.