Project Summary:
The pancreas has several different cell types that secret hormones to regulate blood glucose levels. Type 1 diabetes (T1D) is primarily associated with the autoimmune destruction of the insulin-producing beta cells, which are responsible for lowering blood glucose levels. However, there is growing evidence that alpha cells, which secrete glucagon to raise blood glucose levels, no longer function properly in patients with T1D. Since both cell types work together to maintain proper blood glucose levels, it is important to understand how beta and alpha cells function in the context of T1D. Proper function of alpha cells is largely regulated at the molecular level by several DNA-binding proteins that are responsible for turning on and off important cell-specific genes. When there is dysregulation at this level, key genes are not able to be turned on or off. As a result, the cells become dysfunctional, contributing to disease progression.
Dr. Januszkiewicz recently identified KLF4 as an important DNA-binding protein essential for proper alpha cell identity and function in mice. Removing this protein from the alpha cells results in decreased expression of key alpha cell genes. While KLF4 is known to regulate gene expression, it’s precise role in maintaining alpha cell identity and function remains unclear.
The goal of Dr. Januszkiewicz’s project is to characterize the function of KLF4 in alpha cell function using state-of-the-art T1D models and human stem cell-derived islet cells. Through a combination of approaches, he seeks to understand the underlying roles of this important protein in the alpha cells and how it might contribute to T1D disease progression when dysregulated. Understanding how KLF4 regulates alpha cell identity and function in the context of T1D could provide valuable insights into disease mechanisms and potential therapeutic strategies.
