Objective
Our objective is to investigate whether randomly acquired mutations are enriched in the insulin-producing pancreatic β-cells or immune cells of individuals with or at-risk for type 1 diabetes (T1D). In addition to investigation of overall mutation rates, we intend to identify the genes and pathways in which variants are enriched. We hypothesize that somatic mutations contribute to T1D by enhancing the fragility of insulin-producing pancreatic β-cells or promoting the survival or proliferation of immune cells.
Background Rationale
Type 1 diabetes (T1D) is mediated by genetic, environmental, and stochastic factors. Somatic variants, random mutations acquired after conception, have been shown to play an important role in the development of cancer and other autoimmune diseases. There is evidence to suggest that DNA damage in insulin-producing pancreatic β-cells contributes to the development of T1D and we know that DNA damage leads to randomly acquired somatic mutations. The stochastic nature of somatic variants may also explain why some islets are destroyed and others are not within the same T1D donor. Immune cells from the mouse model of T1D have also been shown to carry randomly acquired mutations. However, somatic mutations have yet to be thoroughly investigated in the tissues of organ donors affected by or at-risk for T1D.
Description of Project
Background: Type 1 diabetes (T1D) is mediated by genetic, environmental, and stochastic factors. Somatic variants, random mutations acquired after conception, have been shown to play an important role in the development of cancer and other autoimmune diseases. There is evidence to suggest that DNA damage in insulin-producing pancreatic β-cells contributes to the development of T1D and we know that DNA damage leads to randomly acquired somatic mutations. The stochastic nature of somatic variants may also explain why some islets are destroyed and others are not within the same T1D donor. Immune cells from the mouse model of T1D have also been shown to carry randomly acquired mutations. However, somatic mutations have yet to be thoroughly investigated in the tissues of organ donors affected by or at-risk for T1D. Therefore, we hypothesize that somatic mutations contribute to T1D by enhancing the fragility of insulin-producing pancreatic β-cells or promoting the survival and proliferation of immune cells.
Objective: Our objective is to investigate whether randomly acquired mutations are enriched in the insulin-producing pancreatic β-cells or immune cells of individuals with or at-risk for T1D.
Approach: To identify somatic variants, we will apply sophisticated computational algorithms that have been created for the characterization of cancer genetics to data from pancreatic organ donors as well as living donors at varying stages of T1D. In addition to comparing mutations across stages of disease, we will assess relationships between variants and clinical factors to understand if this phenomenon tends to affect particular donor subgroups. Mutation rates will be evaluated for enrichment at the level of individual mutations, genes, and pathways. We will analyze several complementary datasets to look for overlapping hits for validation.
Anticipated Outcomes: Together, these studies are anticipated to identify genetic variants affecting specific genes or pathways that accumulate in tissues involved in T1D. In the future, we plan to genetically engineer cells to express these identified mutations to investigate their impacts on pancreatic β-cell and immune cell function. We expect that these studies may inspire new therapeutic strategies to prevent or suspend T1D by regulating or correcting somatic mutations.
Anticipated Outcome
These studies are anticipated to identify genetic variants affecting specific genes or pathways that accumulate in insulin-producing pancreatic β-cells and immune cells during the development of type 1 diabetes (T1D). In the future, we plan to genetically engineer cells to express these identified mutations to investigate their impacts on pancreatic β-cell and immune cell function. We expect that these studies may inspire new therapeutic strategies to prevent or suspend T1D by regulating or correcting somatic mutations.
Relevance to T1D
The proposed studies are directly relevant to improving our understanding of the basic mechanisms controlling β-cell and immune cell function in type 1 diabetes (T1D). By applying concepts and tools generated by researchers in other fields, we may discover novel genes and pathways disrupted during the development of T1D. Knowledge generated by these studies may provide support for testing therapeutics from the aging or cancer fields in T1D.