Objective
The goal of this project is to understand how a gene called RPS26 influences the health and survival of insulin-producing beta cells in type 1 diabetes (T1D). In T1D, the immune system mistakenly attacks and destroys these beta cells, making it impossible for the body to produce enough insulin to keep blood sugar levels in a healthy range.
Our recent large-scale genetic studies have identified natural differences in the RPS26 gene that are linked to an increased risk of developing T1D. RPS26 makes a protein that helps cells build other proteins accurately and efficiently. When this process is disturbed, errors can occur that stress beta cells and make them more visible to the immune system, leading to their attack and destruction.
In this project, we will use state-of-the-art genetic and molecular tools to study how changes in RPS26 affect beta-cell health, stress responses, and immune recognition, with the goal of discovering new ways to protect beta cells and slow the progression of T1D.
Background Rationale
Type 1 diabetes (T1D) develops when the body’s immune system mistakenly attacks and destroys the insulin-producing beta cells in the pancreas. Without beta cells, the body cannot make insulin to regulate blood sugar, leading to lifelong dependence on insulin therapy. Although genetic factors are known to contribute to T1D risk, how these genetic differences make beta cells specifically targeted for immune destruction remains poorly understood.
Our preliminary studies suggest that genetic variation in a gene called RPS26 may provide an important new clue to why beta cells become vulnerable to immune attack. RPS26 helps cells synthesize proteins accurately and efficiently. When this process is disrupted, errors in protein production can stress beta cells and cause them to display abnormal protein fragments that attract immune attack.
We believe that natural genetic differences in RPS26 alter how faithfully beta cells make proteins, increasing cellular stress and making them more likely to trigger autoimmunity in T1D. Studying this mechanism may reveal a previously unrecognized pathway that connects genetic risk to beta-cell destruction and disease development.
Description of Project
Type 1 diabetes (T1D) develops when the immune system mistakenly attacks and destroys the insulin-producing beta cells in the pancreas. Once beta cells are lost, the body can no longer produce insulin to keep blood sugar within normal levels, requiring lifelong insulin treatment. A central question in diabetes research is why beta cells are selectively targeted and destroyed while other pancreatic cells are spared. T1D also has a strong hereditary component, yet how genetic factors make beta cells more vulnerable to immune attack remains unclear.
Our research using large-scale human genetic data has identified that genetic factors regulating the expression of the RPS26 gene are associated with T1D risk. RPS26 produces a protein that helps cells synthesize other proteins accurately and efficiently. This “quality control” in protein production is critical for maintaining healthy cell function, and when it fails, misfolded or abnormal proteins can accumulate, causing stress and triggering immune responses.
This project will uncover how natural genetic variation in RPS26 and its expression levels influence beta-cell health and immune recognition. We will use genetically engineered human beta-cell models to study how RPS26 affects the accuracy and efficiency of protein synthesis, stress responses, and the display of immune “signals” that provoke autoimmunity. We will also analyze genetic and clinical data from large human cohorts to determine how RPS26 variation relates to beta-cell function over time in people with T1D.
By connecting genetics to cell biology, this study aims to establish RPS26 as a potential therapeutic target for strengthening beta-cell resilience and slowing the progression of T1D.
Anticipated Outcome
We expect this project to reveal how natural genetic differences in the RPS26 gene influence the health and survival of insulin-producing beta cells in type 1 diabetes (T1D). The findings are likely to show that changes in RPS26 expression disrupt the normal process of protein production within beta cells, leading to cellular stress and making these cells more prone to immune attack.
By connecting human genetics with beta-cell biology, this research is expected to identify RPS26 as a key gene contributing to beta-cell fragility and autoimmunity in T1D. Understanding this mechanism will provide a new biological explanation for how inherited genetic variation increases the risk of developing the disease.
Ultimately, these insights could guide the development of therapies that strengthen beta-cell resilience and help prevent or slow immune-mediated destruction in people with or at risk for T1D.
Relevance to T1D
Type 1 diabetes (T1D) remains a lifelong disease with no definitive prevention or cure. It results from the immune system’s destruction of insulin-producing beta cells in the pancreas. Current treatments replace insulin but do not address why beta cells are attacked or how to protect them from immune damage.
This project takes a new approach by studying a gene called RPS26, which helps beta cells make proteins accurately and efficiently. Our findings suggest that natural genetic differences in RPS26 may disrupt this process, causing stress inside beta cells and making them more vulnerable to immune attack.
By revealing how RPS26 contributes to beta-cell stress and immune recognition, this research could uncover a previously unrecognized pathway that explains part of the genetic risk for T1D. Ultimately, these discoveries may guide the development of therapies that strengthen beta-cell health and resilience, and offering the potential to delay, prevent, or lessen the severity of T1D in those genetically at risk, and to improve long-term outcomes for people already living with the disease.