Grant: Operating Grant

Erythropoietin (Epo) is largely known for its role in erythropoiesis. However, recent studies have reported the presence of the Epo receptor (EpoR) on non-erythroid tissues, including the neuronal cells, the kidney, the heart, and the pancreatic beta cells. These findings have led to further investigations of the possible non-hematopoietic effects of Epo. Indeed, emerging evidence shows cytoprotective roles of Epo in neuronal and other tissue injury models. The non-hematopoietic roles of Epo in pancreatic beta cells and in diabetes is not well understood. The objective of our study is to investigate the direct effects of Epo on the pancreatic beta cells during physiological and diabetic states. We hypothesize that Epo can directly promote beta cell survival and growth, and protect against diabetes development through activation of its receptor and downstream signaling pathways. In order to assess the direct effects of Epo on the beta cells, we will investigate the essential roles of EpoR and its immediate downstream signaling molecule JAK2 (Janus kinase 2) specifically in the pancreatic beta cells by using beta cell-specific knockout mice. These mice will be examined during their normal growth to assess the role of endogenous Epo during normal physiological growth of the pancreatic beta cells. We will also study the role of endogenous and exogenous Epo during models of diabetes. Our proposed experiments will determine the physiological roles of Epo in promoting beta cell growth and survival, and identify Epo or Epo-related agents as potential novel therapeutic targets for diabetes.