Objective
The objective of this research is to understand the molecular mechanisms that govern the development and survival of insulin-binding B cells in the bone marrow and their release into the circulation from where they mature to play a crucial role in the development of T1D. By better understanding these mechanisms, the researchers hope to reduce the production of harmful B cells and preserve insulin production, leading to improved outcomes for people newly diagnosed with T1D. These studies will measure the activity of the PI3K pathway in bone marrow B cells of T1D patients and healthy individuals and determine the correlation between this activity level and the bone marrow release into the blood of insulin-binding B cells. They will also compare gene expression in insulin-binding and non-binding bone marrow B cells newly released into the blood between T1D patients and healthy individuals to identify pathways that correlate with the production of harmful B cells. Finally, these studies will use mouse models harboring human B cells and also blood samples from patients harboring PI3K genetic variants or relevant pharmacological treatments to validate whether targeting the PI3K pathway modulates the production of insulin-binding B cells.
Background Rationale
Type 1 diabetes (T1D) is a serious autoimmune disease in which the body's immune system mistakenly attacks and destroys the cells in the pancreas that produce insulin. This leads to a lifelong dependence on insulin replacement therapy to maintain glucose levels in the body. The goal of this research project is to improve outcomes for individuals newly diagnosed with T1D (or at risk for T1D) by developing strategies to reduce the immune response directed towards insulin-producing beta cells and preserve insulin production. B cells play a crucial role in T1D by producing antibodies that attack insulin and other important proteins in the pancreas. In healthy individuals, B cells are controlled by mechanisms that prevent them from attacking the body's own proteins and cells, but T1D patients have defects in these mechanisms. Studies in animal models have shown that a specific signaling pathway called the phosphatidylinositol 3-kinase (PI3K) pathway regulates the production of B cells in the bone marrow, which is lifelong. This pathway is responsible for stopping the generation of harmful B cells and releasing non-harmful B cells into circulation. We hypothesize that defects in the PI3K pathway or related biochemical pathways are present in T1D patients and lead to increased development of harmful B cells that attack insulin and other self-molecules. We also hypothesize that targeting this pathway may reduce the generation of these harmful B cells and support the maintenance of insulin production in individuals at risk for T1D or newly diagnosed with this disease.
Description of Project
Type 1 diabetes (T1D) is a disease in which the body's immune system attacks and destroys insulin-producing cells in the pancreas. This leads to a lifetime need for insulin replacement therapy to survive. B cells are a major component of the immune system and are the cells responsible for the production of antibodies. It has well accepted that B cells play a crucial role in T1D by producing antibodies that attack insulin and other important proteins in the pancreas. In healthy individuals, B cells are controlled by mechanisms that prevent them from attacking the body's own proteins, but T1D patients have defects in these mechanisms. Studies in animal models have shown that a specific biochemical pathway called the phosphatidylinositol 3-kinase (PI3K) pathway regulates the lifelong production of B cells in the bone marrow. This pathway is responsible for stopping the production of harmful B cells and releasing non-harmful B cells into circulation. We hypothesize that defects in the PI3K pathway present in T1D patients lead to increased production of insulin-binding B cells that promote and facilitate immune responses against the pancreas. We also propose that targeting the PI3K pathway may reduce the development of these harmful B cells and support the maintenance of insulin production. The findings of these studies have the potential to translate into therapies that reduce the generation of harmful B cells and support the maintenance of insulin production in newly diagnosed T1D patients and at risk individuals. This research aims to improve outcomes for individuals newly diagnosed with T1D and provide a better understanding of the mechanisms that lead to the disease.
Anticipated Outcome
The goal of this research project is to find a way to reduce the immune response that attacks and destroys the insulin-producing cells in the pancreas in people at risk for, or newly diagnosed with Type 1 Diabetes (T1D). These studies aim to understand the biochemical mechanisms that govern the lifelong production of insulin-binding B cells in the bone marrow of T1D patients and to determine whether targeting these mechanisms reduces the generation of these cells. Specifically, these studies aim to investigate whether the activity of a specific pathway in the body called the phosphatidylinositol 3-kinase (PI3K) pathway, which is known to regulate the production of B cells in the bone marrow, is altered in T1D patients. The anticipated outcomes of this research are to establish whether B cells that develop in the bone marrow of T1D patients have altered activity of the PI3K pathway ¬or of other biochemical/genetic pathways, correlating with the bone marrow release into the blood of insulin-binding B cells and/or their affinity for insulin. They will also provide evidence of whether modulating the activity of elements of the PI3K pathway can be used as a way to decrease the bone marrow release of insulin-binding B cells. Findings from these studies could lead in the near future to test therapies that reduce the lifelong bone marrow development of insulin-reactive B cells and, hence, support maintenance of insulin production in at risk and newly diagnosed T1D subjects.
Relevance to T1D
These studies are relevant to type 1 diabetes because they provide insights into the mechanisms underlying the development and progression of the disease. They suggest that genetic and immunological factors play a role in the onset of type 1 diabetes and provide a basis for the development of new treatments and prevention strategies. The findings of these studies can also help identify individuals who are at higher risk of developing type 1 diabetes and inform the development of early intervention and management programs.