Michael L. McDaniel, Ph.D.

DEPARTMENT OF Pathology & Immunology
Keywords: diabetes, transplantation, DNA replication, mTOR, pancreatic islets

The focus of our laboratory is to define metabolic signaling pathways that mediate cell growth and proliferation in adult human and rodent islets. Stimulating islet beta-cells to proliferate is a clinical goal that could have a beneficial impact on both type 1 diabetes for ex vivo transplantation protocols and in type 2 diabetes for approaches that generate beta-cell replication in vivo. Mammalian Target of Rapamycin (mTOR) is a unique protein kinase that integrates signals derived from growth factors and nutrients to regulate cell growth and proliferation. Our previous studies have demonstrated that nutrients stimulate mTOR-mediated DNA synthesis and cell cycle progression, prerequisite events required for mitosis, in rodent islets but are rarely effective in human islets.

Our recent findings have identified glycogen synthase kinase-3 (GSK-3) as a key component in the regulation of mTOR-dependent regenerative processes. Remarkably, a highly specific GSK-3 inhibitor or lithium possess the unique ability to stimulate mTOR-dependent DNA synthesis and promotion of cells to enter the cell cycle in human islets. Our ongoing studies will utilize molecular and genetic approaches to understand the transcriptional and translational signals that facilitate GSK-3/mTOR-mediated regenerative processes necessary to expand human beta-cells ex vivo.