The Gu laboratory studies the developmental biology of the pancreas in both mouse and chicken models. The vertebrate pancreas has two functions: providing digestive enzymes for food digestion and endocrine hormones for regulating energy metabolism. The exocrine pancreas, comprised of acinar and pancreatic duct cells perform the former function. The endocrine islets of Langerhans secrete hormones into the blood stream for the latter. 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. Our goals are to unravel the molecular and cellular mechanisms regulating pancreatic development and endocrine islet cell function, and translate these basic understandings to therapeutic strategies for diabetes.
Our current studies centered on the factor/pathways that regulate the differentiation of pancreatic progenitors to beta cells, beta cell maturation/insulin secretion, and beta cell functional maintenance.
1) Allocation of pancreatic progenitors to pancreatic beta cells. All pancreatic cells derive from a common set of endodermal pancreatic progenitors in later gestation. We ask why a specific portion of these progenitors becomes beta cells. By designing innovative tool and utilizing elegant genetic studies, we explore how cell-cell communications via membrane proteins restrict the activation of a proendocrine gene, Neurogenin 3, in a specific number of cells to activate their endocrine program. We then determine the combination of transcription factors and mechanisms that specify particular progenitors to beta cell fate.
2) Controlling beta cell maturation and insulin secretion. When beta cells were first made, i.e. when insulin vesicles are first achieved in cells, they do not secrete insulin when stimulated with nutrients. These immature cells have to re-organize their molecular machinery to make cells glucose responsive. By examining the gene expression pattern and correlate them with insulin secretion, we have revealed several genetic networks, including the factors that regulate neural transmission, that accompany beta cell maturation. We are testing whether manipulating these pathways expedite beta cell maturation by facilitating insulin secretion. Furthermore, we also collaborate with colleagues to examine whether the cytoskeletal networks in beta cells paly any roles in insulin secretion regulation.
3) Beta cell mass maintenance. In postnatal life, beta cells proliferate to compensate for bodily growth and beta cell death, so that a specific beta cell mass is maintained in each individual. By examining beta cell division and mass, we have found that there is an inverse relationship between beta cell proliferation and the insulin secretion capability of beta cells. We are currently pursuing a hypothesis that an autocrine mechanism is utilized to ensure that each individual to produce a sufficient amount of insulin secreting ability (i.e. a combination of beta cell mass and secreting efficiency). We also investigate the mechanisms underlying beta cell survival. We have revealed a Myt1 transcription factor-organized pathway that maintains beta cell survival during insulin secretion. We envision that this mechanism is highly relevant to the development of Type II diabetes in human subjects, which is postulated to be a matter of beta cell death induced by over insulin secretion.
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MeSH terms are retrieved from PubMed records. Learn more.
Key: MeSH Term KeywordAcinar Cells adult pancreatic progenitor during regeneration Aging Alleles Aquaporin 2 Benzofurans beta cell death Biliary Tract Blood Glucose cell division Cell Line, Tumor cell marking and cell lineage Cell Transformation, Neoplastic Disease Susceptibility DNA endocirne islet cell differentiation and functional maintenance Forkhead Transcription Factors Gene Expression Regulation, Enzymologic Genes, Lethal Glycine Golgi Apparatus Homeostasis Immunohistochemistry In Situ Hybridization Insulin-Secreting Cells Intestine, Small Ligation Nerve Tissue Proteins Pancreatic Hormones Proto-Oncogene Proteins p21(ras) Receptors, Notch regeenration Somatostatin Spatial Behavior Tissue Distribution Vascular Endothelial Growth Factor A