Our hypothesis is that there are demonstrable phenotypic differences between new and mature a cells that will provide important information about beta cell birth and death. Using laser capture microdissection and Affymetrix GeneChips, gene profiling data was generated comparing the beta cell-enriched cores of new and mature islets from the same rats after partial pancreatectomy (Px) and of islets from sham operated animals. The comparison of mature vs. sham islets reflects changes in environment but that between new vs. mature islets reflect age differences. These data show clear effects of age of beta cells on differential gene expression.
The first aim i s to develop markers that can be used for determining beta cell maturity from early stages just as the a cell has differentiated from precursor/stem cells to mature functional a cells. Several such markers have already been confirmed by RT-PCR and immunostaining within the regenerating pancreas as well as with neonatal islets, in which all a cells must be new. These markers will then be used in the second aim to determine the distribution of new and mature beta cells in different aged animals, which should answer fundamental questions about a cell life history. In the third aim these markers will be used to separate new and mature a cells to give relatively pure populations for analysis of their function both in vitro and in vivo following transplantation. With gene profiling of these pure populations the genetic """"""""fingerprints"""""""" of the different stages of the beta cell through its life history will be determined; these fingerprints will be valuable for assessing the maturity of stem cell-derived insulin producing cells and in our future identification of the precursor/stem cells that give rise to a cells after birth. Another important outcome of this research should be valuable information about such practical questions as what will lead to successful long-term islet transplantation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK066056-01A2
Application #
6985823
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Sato, Sheryl M
Project Start
2005-09-15
Project End
2009-07-31
Budget Start
2005-09-15
Budget End
2006-07-31
Support Year
1
Fiscal Year
2005
Total Cost
$290,675
Indirect Cost
Name
Joslin Diabetes Center
Department
Type
DUNS #
071723084
City
Boston
State
MA
Country
United States
Zip Code
02215
Cavelti-Weder, Claudia; Li, Weida; Zumsteg, Adrian et al. (2016) Hyperglycaemia attenuates in vivo reprogramming of pancreatic exocrine cells to beta cells in mice. Diabetologia 59:522-32
Yamada, Takatsugu; Cavelti-Weder, Claudia; Caballero, Francisco et al. (2015) Reprogramming Mouse Cells With a Pancreatic Duct Phenotype to Insulin-Producing ?-Like Cells. Endocrinology 156:2029-38
Sullivan, Brooke A; Hollister-Lock, Jennifer; Bonner-Weir, Susan et al. (2015) Reduced Ki67 Staining in the Postmortem State Calls Into Question Past Conclusions About the Lack of Turnover of Adult Human ?-Cells. Diabetes 64:1698-702
Caballero, Francisco; Siniakowicz, Karolina; Hollister-Lock, Jennifer et al. (2014) Birth and death of human ?-cells in pancreases from cadaver donors, autopsies, surgical specimens, and islets transplanted into mice. Cell Transplant 23:139-51
Cavelti-Weder, Claudia; Shtessel, Maria; Reuss, Joshua E et al. (2013) Pancreatic duct ligation after almost complete ?-cell loss: exocrine regeneration but no evidence of ?-cell regeneration. Endocrinology 154:4493-502
Weir, Gordon C; Aguayo-Mazzucato, Cristina; Bonner-Weir, Susan (2013) ?-cell dedifferentiation in diabetes is important, but what is it? Islets 5:233-7
King, Aileen J F; Guo, Yongjing; Cai, Dongsheng et al. (2013) Sustained NF-?B activation and inhibition in ?-cells have minimal effects on function and islet transplant outcomes. PLoS One 8:e77452
Cantley, James; Walters, Stacey N; Jung, Min-Ho et al. (2013) A preexistent hypoxic gene signature predicts impaired islet graft function and glucose homeostasis. Cell Transplant 22:2147-59
Weir, Gordon C; Bonner-Weir, Susan (2013) Islet ýý cell mass in diabetes and how it relates to function, birth, and death. Ann N Y Acad Sci 1281:92-105
Muscogiuri, Giovanna; Salmon, Adam B; Aguayo-Mazzucato, Cristina et al. (2013) Genetic disruption of SOD1 gene causes glucose intolerance and impairs ?-cell function. Diabetes 62:4201-7

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