Objective
The long-term goal of our work is to develop beta cell regenerative therapies for T1D. Despite recent advances, there are no drugs currently in clinical use to regenerate beta cells. We urgently need new targets to stimulate beta cell regeneration to replace the deficit of cells producing insulin in T1D. Therefore, our current objective is to define the therapeutic potential for a key transcription factor to stimulate human beta cell proliferation.
Background Rationale
Increased metabolic demand is a powerful stimulus for human beta cell proliferation. However, we do not know the specific factors that link beta cell proliferation with metabolism. We previously developed a unique and robust model to study beta cell proliferation in response to increased metabolic demand. Through a series of experiments and bioinformatic analyses, we identified a strong candidate (Gabpa) as the missing link between metabolism and proliferation. However, the function of Gabpa in human beta cells is unknown. Our preliminary findings in mouse beta cells and evidence in the literature further indicate that Gabpa is a convergence point that links metabolism to cell proliferation. Therefore, we hypothesize that Gapba will stimulate human beta cell proliferation
Description of Project
Type 1 diabetes (T1D) is defined by a significant loss of insulin-producing beta cells in the pancreas leading to elevated blood glucose levels. The long-term goal of our work is to develop beta cell regenerative therapies for T1D. Without new approaches to replace beta cells, people living with T1D will remain dependent on insulin therapy to manage their diabetes. Strategies that stimulate beta cell proliferation represent the most durable mechanism to regenerate beta cells. Increased metabolic demand is a powerful stimulus for beta cell proliferation in rodents and humans, as beta cells compensate to meet the need for more insulin. Leveraging this naturally occurring process in humans provides a strong opportunity to identify new targets to activate beta cell proliferation in humans. Obesity, as a model of increased metabolic demand, has been studied at length in rodents, yet the mechanisms connecting increased metabolism to beta cell proliferation are not well understood. We previously established a unique and robust model of beta cell expansion through acute deletion of the gene coding for a satiety hormone receptor. We found durable and remarkable beta cell expansion, even in very old mice. Through single-cell and bioinformatic approaches, we identified a transcription factor (Gabpa) in a sub-population of beta cells poised to proliferate. Previous studies in muscle and fibroblasts suggest Gabpa regulates key metabolic processes and cell proliferation. Our initial mouse studies demonstrate that loss of Gabpa results in impaired beta cell expansion in early life. Collectively, these findings suggest Gabpa is the missing link between metabolism and proliferation in beta cells. Thus, we hypothesized that Gabpa is a pivotal factor capable of driving human beta cell proliferation. Our proposed studies will define the ability of Gabpa to stimulate human beta cell proliferation in pre-clinical models, as well as define the mechanism of Gabpa action in human beta cells. Together, the proposed studies will define the potential of Gabpa targeting as a regenerative therapy for T1D.
Anticipated Outcome
We expect to find that Gabpa stimulates human beta cell proliferation. Based on our preliminary findings and previously described functions in other cell types, we believe Gabpa is a key convergence point for metabolism and cell proliferation. Our studies will identify the gene programs specifically activated by Gabpa and reveal the underlying mechanisms that stimulate beta cell proliferation. Additionally, we expect that Gabpa stimulated human beta cell proliferation will be sufficient to expand beta cells to reverse diabetes in a commonly used pre-clinical mouse model. These findings represent a significant step towards advancing Gabpa targeting for beta cell regeneration in T1D.
Relevance to T1D
Type 1 diabetes (T1D) is defined by a significant loss of insulin-producing beta cells in the pancreas leading to elevated blood glucose levels. We urgently need new approaches to regenerate beta cells to restore glucose control. We have identified a strong therapeutic candidate to expand human beta cells. Our proposed studies will uncover a powerful and durable mechanism that may exert therapeutic benefits to regenerate beta cells for people living with T1D. The ability to regenerate beta cells in T1D would alleviate the need for insulin therapy and significantly improve quality and quantity of life.