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1,556 results on '"Vale, Wylie"'

1. CRFR1 activation protects against cytokine-induced β-cell death

Author

Blaabjerg, Lykke, Christensen, Gitte L, Matsumoto, Masahito, van der Meulen, Talitha, Huising, Mark O, Billestrup, Nils, and Vale, Wylie W

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Diabetes, Autoimmune Disease, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Animals, Apoptosis, Cell Death, Cells, Cultured, Corticotropin-Releasing Hormone, Cytokines, Cytoprotection, Humans, Insulin-Secreting Cells, Interleukin-1beta, Mice, Rats, Receptors, Corticotropin-Releasing Hormone, Tumor Necrosis Factor-alpha, &beta, cells, apoptosis, survival, urocortins, GPCR, CRFR, cytokines, β cells, Veterinary Sciences, Paediatrics and Reproductive Medicine, Endocrinology & Metabolism, Clinical sciences
Abstract

During the development of diabetes β-cells are exposed to elevated concentrations of proinflammatory cytokines, TNFα and IL1β, which in vitro induce β-cell death. The class B G-protein-coupled receptors (GPCRs): corticotropin-releasing factor receptor 1 (CRFR1) and CRFR2 are expressed in pancreatic islets. As downstream signaling by other class B GPCRs can protect against cytokine-induced β-cell apoptosis, we evaluated the protective potential of CRFR activation in β-cells in a pro-inflammatory setting. CRFR1/CRFR2 ligands activated AKT and CRFR1 signaling and reduced apoptosis in human islets. In rat and mouse insulin-secreting cell lines (INS-1 and MIN6), CRFR1 agonists upregulated insulin receptor substrate 2 (IRS2) expression, increased AKT activation, counteracted the cytokine-mediated decrease in BAD phosphorylation, and inhibited apoptosis. The anti-apoptotic signaling was dependent on prolonged exposure to corticotropin-releasing factor family peptides and followed PKA-mediated IRS2 upregulation. This indicates that CRFR signaling counteracts proinflammatory cytokine-mediated apoptotic pathways through upregulation of survival signaling in β-cells. Interestingly, CRFR signaling also counteracted basal apoptosis in both cultured INS-1 cells and intact human islets.

Published
2014

2. Urocortin 3 Marks Mature Human Primary and Embryonic Stem Cell-Derived Pancreatic Alpha and Beta Cells

Author

van der Meulen, Talitha, Xie, Ruiyu, Kelly, Olivia G, Vale, Wylie W, Sander, Maike, and Huising, Mark O

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Stem Cell Research, Regenerative Medicine, Stem Cell Research - Embryonic - Human, Diabetes, Autoimmune Disease, Animals, Cell Differentiation, Cell Lineage, Embryonic Stem Cells, Gene Expression, Glucagon-Secreting Cells, Homeodomain Proteins, Humans, Immunohistochemistry, Insulin-Secreting Cells, Islets of Langerhans, Mice, Trans-Activators, Urocortins, General Science & Technology
Abstract

The peptide hormone Urocortin 3 (Ucn 3) is abundantly and exclusively expressed in mouse pancreatic beta cells where it regulates insulin secretion. Here we demonstrate that Ucn 3 first appears at embryonic day (E) 17.5 and, from approximately postnatal day (p) 7 and onwards throughout adult life, becomes a unifying and exclusive feature of mouse beta cells. These observations identify Ucn 3 as a potential beta cell maturation marker. To determine whether Ucn 3 is similarly restricted to beta cells in humans, we conducted comprehensive immunohistochemistry and gene expression experiments on macaque and human pancreas and sorted primary human islet cells. This revealed that Ucn 3 is not restricted to the beta cell lineage in primates, but is also expressed in alpha cells. To substantiate these findings, we analyzed human embryonic stem cell (hESC)-derived pancreatic endoderm that differentiates into mature endocrine cells upon engraftment in mice. Ucn 3 expression in hESC-derived grafts increased robustly upon differentiation into mature endocrine cells and localized to both alpha and beta cells. Collectively, these observations confirm that Ucn 3 is expressed in adult beta cells in both mouse and human and appears late in beta cell differentiation. Expression of Pdx1, Nkx6.1 and PC1/3 in hESC-derived Ucn 3(+) beta cells supports this. However, the expression of Ucn 3 in primary and hESC-derived alpha cells demonstrates that human Ucn 3 is not exclusive to the beta cell lineage but is a general marker for both the alpha and beta cell lineages. Ucn 3(+) hESC-derived alpha cells do not express Nkx6.1, Pdx1 or PC1/3 in agreement with the presence of a separate population of Ucn 3(+) alpha cells. Our study highlights important species differences in Ucn 3 expression, which have implications for its utility as a marker to identify mature beta cells in (re)programming strategies.

Published
2012

24. Chronic Activation of Corticotropin-Releasing Factor Type 2 Receptors Reveals a Key Role for 5-HT1A Receptor Responsiveness in Mediating Behavioral and Serotonergic Responses to Stressful Challenge

Author

Neufeld-Cohen, Adi, Kelly, Paul A.T., Paul, Evan D., Carter, Roderick N., Skinner, Elizabeth, Olverman, Henry J., Vaughan, Joan M., Issler, Orna, Kuperman, Yael, Lowry, Christopher A., Vale, Wylie W., Seckl, Jonathan R., Chen, Alon, and Jamieson, Pauline M.

Published
2012
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