Objective
The long-term research goal of our program is to address the role of the β-cell UPR in T1D pathophysiology. The overall objective of this project is to determine the function of XBP1 during different stages of T1D disease progression using a well-established T1D preclinical model.
Background Rationale
While most preclinical studies have focused primarily on immunotherapy due to the autoimmune nature of T1D, β-cells have long been considered as the “innocent victim cells” in T1D pathogenesis. However, emerging data indicate the important contribution of β-cells to the disease pathology. The link between ER stress and β-cell-function and survival has been investigated extensively over the past 2 decades by multiple research groups. However, these studies were performed in cell culture systems or healthy mouse models hindering our understanding of the precise role of β-cell ER stress and the UPR in a complex disease like T1D. To circumvent this, we have generated genetically modified stress response gene models on a T1D mouse model. This will allow us to discover specific functions of stress response genes during different stages of disease. In the proposed study, we will use a comprehensive toolbox of state-of-the-art techniques, a novel mouse model, and a pharmacological tool to decode function of XBP1 in β-cells of a T1D mouse model. The primary impact of this proposal is the identification of the function and modulation of a stress response program in β-cells of NOD mice during disease progression.
Description of Project
Type 1 diabetes (T1D) results from an autoimmune-mediated destruction of insulin-producing pancreatic β-cells and affects approximately 3 million people in the United States and 10-20 million worldwide. The rapidly increasing incidence of T1D, as much as 3-5% per year, is of great concern. Currently there is no way to cure or prevent T1D, hence a deeper understanding of the underlying molecular mechanisms of this disease is essential to the development of new therapies. Endoplasmic reticulum (ER) stress, caused by protein misfolding, chronic inflammation, and environmental factors, plays an important role in the etiology of the inflammatory diseases. We previously demonstrated that β-cells of mouse models of T1D as well as T1D patients exhibit ER stress, and abnormal unfolded protein response (UPR). Remarkably, mitigation of ER stress and restoration of aberrant UPR can prevent T1D in two different T1D preclinical models. These findings suggest that targeting ER can be a plausible therapeutic strategy for T1D. Building on our previous work and based on our preliminary data, here we propose to unveil the function of one of the key UPR sensors, XBP1, in β-cells of a T1D preclinical model at prediabetic stage. We will perform genetic and pharmacological studies to determine how β-cell function and survival are affected when XBP1 activity is increased or abolished in a T1D model. This work has the potential to make an important impact on our understanding of the role of the β-cell UPR in T1D and promote development of better therapeutic and preventive strategies against T1D.
Anticipated Outcome
Upon completion of this work, we will definitively demonstrate for the first time a key UPR gene's β-cell-cell specific functions during different stages of disease progression. In this manner, we will produce comprehensive and integrated data that will greatly enhance our understanding of the role of organelle dysfunction in T1D etiology. The results of our work will be far-reaching, shedding light on a previously unappreciated aspect of β-cell failure in T1D and providing a mechanistic understanding that will potentially translate into the development of β-cell-based therapeutic strategies or combination therapies with immune-based approaches. The research proposed here is also significant in terms of broader, translational importance because it will provide substantial biological understanding for other common diseases that share similar organelle failure and aberrant stress responses in their etiology such as obesity, type 2 diabetes, atherosclerosis, neurodegenerative disorders, and cancer.
Relevance to T1D
T1D, with an alarming increase in incidence, calls for immediate development of new and more effective therapeutic regimens for prevention or curing of the disease. By using a recently generated mouse model, this proposal aims to identify the function of the β-cell unfolded protein response during the progression of T1D. This study is relevant to T1D because it will advance our understanding of the role of β-cell endoplasmic reticulum stress in T1D diabetes pathogenesis and provide a basis for preventing β-cell inflammatory responses, dysfunction, and death. The knowledge that will be gained from the proposed work has the potential to develop novel therapeutic strategies.