Diabetes mellitus results from loss or dysfunction of the insulin-producing beta-cells in the pancreas. Despite refined insulin injection regimens, diabetic patients suffer from long-term complications, such as blindness and kidney failure. An ultimate cure for diabetes could be achieved through the generation of replacement insulin-producing cells. To develop these replacement cells, we need to identify the molecular pathways that initiate beta-cell formation and insulin-production. Using genetically engineered mouse models, this proposal examines the role of NKX6 class transcription factors in beta-cell differentiation and function. The specific hypothesis is that different NKX6 transcription factors partially compensate for each other's function in pancreatic cell differentiation. This hypothesis is based on the observation that beta-cell numbers are diminished in Nkx6.1 mutant mice, while Nkx6.1/Nkx6.2 double mutant mice show a reduction in both insulin producing beta- and glucagon-producing alpha-cells. Experiments are proposed to dissect the role of NKX6 factors in pancreatic endocrine development using compound mouse mutants for Nkx6 genes.
Aim 1 is to define the role of NKX6 factors in the beta-cell differentiation pathway by attempting to restore beta-cell development in Nkx6.1 mutant mice with different transgenes.
Aim 2 examines in mice if pancreatic progenitors are reverted into alternate cellular fates in the absence of NKX6 activity.
Aim 3 focuses on the role of NKX6 factors in adult beta-cell function. Using selective inactivation of Nkx6 genes in beta-cells, it will be studied if NKX6 factors control aspects of beta-cell function, such as insulin synthesis or insulin secretion.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK068471-03
Application #
7071866
Study Section
Endocrinology Study Section (END)
Program Officer
Sato, Sheryl M
Project Start
2004-06-01
Project End
2009-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
3
Fiscal Year
2006
Total Cost
$323,936
Indirect Cost
Name
University of California Irvine
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Wortham, Matthew; Benthuysen, Jacqueline R; Wallace, Martina et al. (2018) Integrated In Vivo Quantitative Proteomics and Nutrient Tracing Reveals Age-Related Metabolic Rewiring of Pancreatic ? Cell Function. Cell Rep 25:2904-2918.e8
Cigliola, Valentina; Ghila, Luiza; Thorel, Fabrizio et al. (2018) Pancreatic islet-autonomous insulin and smoothened-mediated signalling modulate identity changes of glucagon+ ?-cells. Nat Cell Biol 20:1267-1277
Serrill, Jeffrey D; Sander, Maike; Shih, Hung Ping (2018) Pancreatic Exocrine Tissue Architecture and Integrity are Maintained by E-cadherin During Postnatal Development. Sci Rep 8:13451
Ediger, Benjamin N; Lim, Hee-Woong; Juliana, Christine et al. (2017) LIM domain-binding 1 maintains the terminally differentiated state of pancreatic ? cells. J Clin Invest 127:215-229
Zeng, Chun; Mulas, Francesca; Sui, Yinghui et al. (2017) Pseudotemporal Ordering of Single Cells Reveals Metabolic Control of Postnatal ? Cell Proliferation. Cell Metab 25:1160-1175.e11
Shih, Hung Ping; Panlasigui, Devin; Cirulli, Vincenzo et al. (2016) ECM Signaling Regulates Collective Cellular Dynamics to Control Pancreas Branching Morphogenesis. Cell Rep 14:169-79
Barrionuevo, Francisco J; Hurtado, Alicia; Kim, Gwang-Jin et al. (2016) Sox9 and Sox8 protect the adult testis from male-to-female genetic reprogramming and complete degeneration. Elife 5:
Gholkar, Ankur A; Senese, Silvia; Lo, Yu-Chen et al. (2016) The X-Linked-Intellectual-Disability-Associated Ubiquitin Ligase Mid2 Interacts with Astrin and Regulates Astrin Levels to Promote Cell Division. Cell Rep 14:180-8
Wortham, M; Sander, M (2016) Mechanisms of ?-cell functional adaptation to changes in workload. Diabetes Obes Metab 18 Suppl 1:78-86
Kopp, Janel L; Grompe, Markus; Sander, Maike (2016) Stem cells versus plasticity in liver and pancreas regeneration. Nat Cell Biol 18:238-45

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