Objective
The long-term research goal of our program is to address the role of the β-cell-immune cell interactions in T1D pathophysiology. The overall objective of this project is to define how UPR-deficiency-induced senescence impact immune cell types, dynamics, and their molecular signatures as disease progresses and whether these responses show sex-dependent differences in a well-established T1D preclinical model.
Background Rationale
While most pre-clinical 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. Studies from various groups showed that senescent cells can alter immune function and surveillance. However, mechanisms of immune surveillance and its regulation remain unknown. Therefore, mapping islet-resident immune cell types transcriptome and epigenetic changes at different time points of T1D progression at the single cell level using cutting-edge technologies would not only advance our understanding of the complex pathophysiology of T1D, but also pave the way for the development of alternative therapeutic strategies against this disease. In the proposed study, we will use a comprehensive toolbox of state-of-the-art techniques and novel mouse (both male and female) models to decode stress induced β-cell senescence and its impact on the local immune subtypes in a preclinical model of T1D.
Description of Project
Type 1 diabetes (T1D) results from insulin insufficiency owing to near complete destruction of insulin-producing pancreatic β-cells by an autoimmune process. Over the last decade, the active participation of pancreatic β-cells in their own autoimmune destruction and the impact of aberrant stress responses to T1D disease progression have gained considerable attention. Pharmacologic agents targeting β-cell stress responses have shown promise in clinical trials, underscoring the potential for targeting β-cell stress in diabetes. Senescence is a stress adaptation program that has recently emerged as a key contributor to T1D pathogenesis. While insufficient clarence of senescence cells by immune system leads their accumulation and detrimental effects, our provocative recent findings show that β-cell senescence induced by unfolded protein response (UPR) deficiency can be protective against T1D by inducing immune clearance of the persistent senescent β-cells in a T1D mouse model. Building on this work, in this proposal we aim to use our recently generated UPR-deficient genetic mouse models to identify the immune cell types that participate in senescent cell clearance and define their molecular signatures at single cell resolution during different stages of disease. We will also take into consideration the potential sex differences in immune response in this study. This work will lay the foundation for follow-up studies to manipulate the dialogue between senescent β-cells and immune cells and have the potential for development of novel intervention strategies.
Anticipated Outcome
Upon completion of this work, we will providea a single-cell atlas of immune cells participating in senescent β-cell-immune cell crosstalk during the different stages of autoimmune diabetes. In this manner, we will produce comprehensive and integrated data that will greatly enhance our understanding of the role of stress responses 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 provide 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 aberrant stress responses in their natural history such as obesity, type 2 diabetes, atherosclerosis, neurodegenerative disorders and cancer.
Relevance to T1D
Targeting senescent β-cells is a relatively new area of investigation for T1D. While studies preclinical models suggest that killing detrimental senescence cells can be protective, systemic effects of this type of treatment remains unclear. An alternative or complementing strategy might be to induce body’s own immunosurveillance system to prevent accumulation of persistent senescence cells. Therefore, it will be crucial to identify the immune subtypes and their molecular signatures that play a role in immunosurveillance. Moreover, sex informed T1D interventions require knowledge of specific factors that help resolve stress in each sex. We anticipate that our proposed work will identify these signatures using unique animals models taking into consideration the sex differences and pave the way for future translational studies.