Objective
The proposed project will apply a multidisciplinary approach combining studies on cellular model systems, pancreatic tissues from human donors, and blood samples from individuals with type 1 diabetes (T1D) to investigate how the cathepsins are involved in the β-cell destruction in T1D and to further explore their clinical potential in predicting the onset of T1D. The project has two specific aims: 1) Investigate the cell type specificity and protein expression of dysregulated cathepsins in the pancreatic islets during T1D, and 2) Examine the diagnostic and prognostic biomarker potential of cathepsin S in new-onset T1D. In the biomarker studies, cathepsin S will be analyzed in serum/plasma from three T1D studies: 1) adults and 2) children/adolescents with new-onset T1D to evaluate its association with treatment, inflammation, and β-cell function, and 3) children before/after seroconversion and T1D to evaluate if it can predict T1D onset. This collaborative project brings together investigators from different research fields, such as T1D, β-cell biology, pediatrics, and endocrinology.
Background Rationale
TType 1 diabetes (T1D) is a chronic autoimmune disease that develops because the insulin-producing β cells in the pancreas are destroyed by the immune system. More than 9 million individuals worldwide are living with T1D, and the incidence is rising at an alarming rate. As a result of the disease, the individuals are depending on lifelong treatment with insulin to sustain life. Many individuals with T1D experience long-term debilitating complications and reduced life expectancy. Despite the great progress made in understanding the underlying mechanisms of the disease, the precise causes of T1D are still unknown, and the disease is neither preventable nor curable. Identification of novel biomarkers and therapeutic targets is necessary to preserve the β cells in individuals with pre- and new-onset T1D. The cathepsin protease family consists of 15 members which are involved in a variety of cellular functions and pathological processes. Accumulating research from our group and others indicate that cathepsins are implicated in the development and progression of T1D. Preliminary data indicate that cathepsins are dysregulated within the pancreatic tissue during T1D and associate with disease duration. A recent study from our group demonstrates that cathepsin S is induced and secreted from the pancreatic β cells during T1D development, and that elevated cathepsin S levels are present in the circulation of individuals with new-onset T1D and high-risk siblings. The data demonstrates a promising early biomarker potential for cathepsin S in T1D.
Description of Project
Type 1 diabetes (T1D) is a chronic autoimmune disease that develops due to a gradual immune-mediated destruction of the insulin-producing β cells in the pancreas, leading to increased blood glucose, severe complications, and reduced life expectancy. Over 9 million people worldwide have T1D. The exact mechanisms underlying T1D are poorly understood, and the disease is neither preventable nor curable. Identification of novel biomarkers and therapeutic targets is necessary to preserve the β cells in individuals with pre- and new-onset T1D. Research indicates that a group of proteins, known as cathepsins, play important roles in the development and progression of T1D. Preliminary data indicate that cathepsins are dysregulated within the pancreatic tissue during T1D and associate with disease duration. A recent study from our group indicates that cathepsin S is induced and secreted from the pancreatic β cells during T1D development, and that elevated cathepsin S levels are present in the circulation of individuals with new-onset T1D and high-risk siblings. Together, the preliminary and published data demonstrate a promising biomarker potential for cathepsin S in relation to the onset of T1D. Using cellular model systems of β cells and immune cells, pancreatic tissues from human donors, and blood samples from individuals with T1D, the project aims to investigate how cathepsins are involved in the β-cell demise in T1D and to further explore the clinical potential of cathepsin S as a predictor of T1D. This multidisciplinary and collaborative project will increase our knowledge of the disease mechanisms in T1D. Importantly, it provides a basis for development of future prevention and intervention strategies and better clinical care for patients with T1D.
Anticipated Outcome
The published and preliminary data demonstrate a great clinical potential for cathepsin S and its family members, which this project proposes to explore further. We anticipate that the project will help unravel the underlying disease mechanisms in type 1 diabetes (T1D) by shedding light on the islet cell type expression and localization of the dysregulated cathepsins, both under physiological and pathological conditions. The societal and commercial implications of this research are significant, potentially leading to the identification of new therapeutic targets for pre-clinical trials and novel biomarkers that could advance the development of more sophisticated diagnostic tools. These advancements could enable more precise monitoring of disease progression and treatment effectiveness in T1D. Although the proposed project focuses on T1D, the results from the project will also be valuable for researchers with other focus areas, e.g., other autoimmune diseases and type 2 diabetes.
Relevance to T1D
Identification of novel biomarkers and therapeutic targets is necessary to preserve the β cells in individuals with pre- and new-onset T1D. The proposed project could make a broad impact in this field. Cathepsin S may be a marker of islet inflammation or β-cell function in T1D and thus be useful as an early diagnostic biomarker for identification of individuals for inclusion in β-cell-preserving intervention studies. The cathepsins also have potential as future therapeutic targets in T1D. The project is thus well aligned with the Breakthrough T1D Research Priority Area “Prevention”.