Pancreatic islets are extensively vascularized and this is important in their ability to sense the blood glucose and quickly secrete insulin. While islets receive up to 20 times more blood flow than surrounding pancreatic acinar tissue, the molecular factors and mechanisms responsible for islet vascularization are incompletely defined. New experimental evidence indicates that pancreatic islets express a number of angiogenic factors such as vascular endothelial growth factor (VEGF), angiopoietin (Ang), and ephrins, and that interactions between islet and endothelial cells are important in both islet development and vascularization. Pancreatic islet transplantation is an emerging therapy for type 1 diabetes, but major obstacles and gaps in our scientific knowledge preclude islet transplantation from being widely adapted. For example, islet isolation severs vascular connections that must be reestablished through angiogenesis/vasculogenesis; a large number of islets (perhaps the majority) die in the first days after transplantation while islet revascularization is occurring. VEGF is a crucial angiogenic factor in vascular development, angiogenesis in response to ischemia, and tumor-related angiogenesis. Even though pancreatic endocrine and exocrine cells share a common developmental lineage, islet cells have greater VEGF expression and vessel density than surrounding exocrine cells. To test the hypotheses that islet vascularization and revascularization requires production of VEGF-A by pancreatic islet cells, we will: ? 1) Elucidate the role of VEGF-A in pancreatic islet development and function using cell-specific, temporal inactivation of the VEGF-A gene using the Cre-loxP system. 2) Examine how gain or loss of VEGF-A function in pancreatic islets affects islet development and function. 3) Determine if gain or loss of VEGF-A function alters the revascularization, survival, or function of transplanted islets. These results should provide a better understanding of normal islet vascularization and how this affects normal islet development, architecture, and function. Information from the transplantation studies may suggest new therapeutic strategies to improve the rapidity and degree of revascularization of transplanted islets. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK069603-03
Application #
7262610
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Sato, Sheryl M
Project Start
2005-09-01
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
3
Fiscal Year
2007
Total Cost
$291,091
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Dean, E Danielle; Li, Mingyu; Prasad, Nripesh et al. (2017) Interrupted Glucagon Signaling Reveals Hepatic ? Cell Axis and Role for L-Glutamine in ? Cell Proliferation. Cell Metab 25:1362-1373.e5
Dai, Chunhua; Kayton, Nora S; Shostak, Alena et al. (2016) Stress-impaired transcription factor expression and insulin secretion in transplanted human islets. J Clin Invest 126:1857-70
Saunders, Diane; Powers, Alvin C (2016) Replicative capacity of ?-cells and type 1 diabetes. J Autoimmun 71:59-68
Ceddia, Ryan P; Lee, DaeKee; Maulis, Matthew F et al. (2016) The PGE2 EP3 Receptor Regulates Diet-Induced Adiposity in Male Mice. Endocrinology 157:220-32
Zhu, Xiaodong; Hu, Ruiying; Brissova, Marcela et al. (2015) Microtubules Negatively Regulate Insulin Secretion in Pancreatic ? Cells. Dev Cell 34:656-68
Brissova, Marcela; Shostak, Alena; Fligner, Corinne L et al. (2015) Human Islets Have Fewer Blood Vessels than Mouse Islets and the Density of Islet Vascular Structures Is Increased in Type 2 Diabetes. J Histochem Cytochem 63:637-45
Li, Mingyu; Dean, E Danielle; Zhao, Liyuan et al. (2015) Glucagon receptor inactivation leads to ?-cell hyperplasia in zebrafish. J Endocrinol 227:93-103
Kayton, Nora S; Poffenberger, Gregory; Henske, Joseph et al. (2015) Human islet preparations distributed for research exhibit a variety of insulin-secretory profiles. Am J Physiol Endocrinol Metab 308:E592-602
Kang, Li; Dai, Chunhua; Lustig, Mary E et al. (2014) Heterozygous SOD2 deletion impairs glucose-stimulated insulin secretion, but not insulin action, in high-fat-fed mice. Diabetes 63:3699-710
Golson, Maria L; Bush, William S; Brissova, Marcela (2014) Automated quantification of pancreatic ?-cell mass. Am J Physiol Endocrinol Metab 306:E1460-7

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