Department of Cell and Developmental Biology

Research Description

Investigating pancreatic beta cell production and function

The Gu laboratory studies how pancreatic islet beta cells are made and how they function and survive over a long life-span using mouse and human islet models. The impact of these studies is to reveal how beta cells in some individuals will lose function and viability, resulting in reduced functional beta-cell mass and subsequent diabetes in human subjects.

Four major islet cell types reside in the islets. They are alpha, beta, delta, and PP cells that secrete glucagon, insulin, somatostatin, and pancreatic polypeptide, respectively. Dysfunction of endocrine islets, especially the insulin secreting beta cells, results in diabetes. Paradoxically, insulin secretion per se makes beta cells vulnerable to workload-induced death and dysfunction, presumably via over-activation of stress response genes (SRGs). Our goals are to unravel the molecular and cellular mechanisms that allow the generation and maintenance of sufficient functional beta-cell mass in each individual to prevent the development of diabetes.

Our current studies focus on:

1. Establishing how genetic and epigenetic factors pre-determine postnatal functional β-cell mass and the risk of diabetes. It is well established that several metabolic diseases, including diabetes, is greatly influenced by the maternal environments, best known as “Developmental Origin of Health and Disease – DOHaD”. We have shown that modulating the DNA enhancer methylation patterns in islet progenitors can impact the proliferation and secretion capacity of postnatal beta cells. Our follow-up studies are to define the specific epigenetic modifications that predetermine postnatal beta-cell fitness (i.e., the ability to enhance their proliferation and secretion under stimulation).
2. Determining how β-cells selectively repress failure-causing SRGs. For sustainable function, each β cell has to synthesize millions of proinsulin molecules in the ER, with ~20% of these misfolded in the ER, which cause ER stress and dysfunction. High glucose metabolism, the trigger of insulin secretion, will induce overproduction of reactive oxygen species (ROS) that cause beta-cell dysfunction. Thus, beta cells activate stress responses to remove misfolded proteins and ROS. However, the SRGs cannot be overactivated, which would have caused cell dysfunction and/or death. We have shown that a family of transcription factors, (Myelin transcription factors or Myt TFs) guards against SRG overactivation. Our current studies is test if eliminating the Myt TF protection predisposes human β cells to workload-induced failure and diabetes.
3. Determining the mechanisms and physiological roles of MT regulation in β cells. Microtubules (MTs) are tubulin-assembled biopolymers that act as a high way for long-range vesicular transport. Thus, the conventional view is that the β cells use MTs growing out of the centrosome to transport insulin vesicles from the cell interior to underneath the plasma membrane for docking and secretion. In contrast, we recently showed that the beta-cell MTs form a non-directional meshwork that is unsuitable for directional cargo transport, but they act as a “trap” for insulin vesicles to present over secretion. Our current studies for this topic is to examine the molecular players that can regulate MT activities and how MT-deregulation causes β-cell failure and diabetes. He and his collaborator are actively examining the roles of several motor proteins, including kinesins and dyneins, and microtubule associated proteins (MAPS) in this process.

Postdoctoral Positions Available

One postdoctoral position available for studying endocrine islet cell development. Available projects includes: 1) characterizing genes expression during mouse pancreas development; 2) generating transgenic and knockout mice to evaluate gene function for endocrine islet development, beta cell maturation, and functional maintenance; 3) using chicken embryos to screen for genes required for endocrine cell differentiation, and 4) using cell lineage tracing methods to understand islet homeostasis and adult pancreatic stem/progenitor cells.