This application addresses broad Challenge Area 11: Regeneration and specific topic challenge topic 11-DK-105: Transdifferentiation or directed reprogramming of one cell fate to another (e.g., a pancreatic exocrine cell to a pancreatic beta cell). In 2005, rates of pre-diabetes/diabetes approached 40% in the US and this number is projected to rise. Current therapies are inadequate: we cannot prevent the death of beta cells in type II diabetics and pancreas transplant is available to very little type I diabetics. Therefore, the ability to regenerate or preserve the pancreatic beta cell would make an immense clinical impact. The study of the insulin promoter has led to such novel therapies. In mice, the ectopic expression of 3 transcription factors that activate the insulin promoter can convert pancreatic exocrine cells into insulin producing endocrine cells. These intriguing findings show that a program of beta cell differentiation can be co-opted for therapeutic use and that the insulin promoter is a necessary part of this program. We propose to find these new targets for beta cell regeneration and preservation by performing whole genome RNA interference (RNAi) screen for regulators of the insulin promoter in pancreatic beta cells. We have developed a statistically robust, high throughput RNAi screening system for insulin promoter activity and have already begun to identify novel hits. We will complement this functional data set with deep sequencing of the beta cell transcriptome. Finally, we will confirm our hits in vivo using transgenic RNAi mice. This collaborative proposal brings together the resources of a lab with expertise in RNA interference and an immediately adjacent lab with expertise in beta cell biology. At the end of the grant period, we anticipate the identification of at least several novel insulin promoter regulators that will not only heighten our understanding of beta cell biology but will also serve as novel drug targets for diabetes treatment.

Public Health Relevance

In 2005, nearly 40% of the US population had diabetes or pre-diabetes - diseases caused by insulin deficiency. We propose to identify genes that regulate insulin production by the pancreatic beta cell. We hope that these genes could be targets for new diabetes therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
NIH Challenge Grants and Partnerships Program (RC1)
Project #
5RC1DK086290-02
Application #
7936881
Study Section
Special Emphasis Panel (ZRG1-EMNR-C (58))
Program Officer
Silva, Corinne M
Project Start
2009-09-25
Project End
2012-02-29
Budget Start
2010-09-01
Budget End
2012-02-29
Support Year
2
Fiscal Year
2010
Total Cost
$498,851
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Lee, Jessica; Pappalardo, Zachary; Chopra, Deeksha Gambhir et al. (2018) A Genetic Interaction Map of Insulin Production Identifies Mfi as an Inhibitor of Mitochondrial Fission. Endocrinology 159:3321-3330
Pappalardo, Zachary; Gambhir Chopra, Deeksha; Hennings, Thomas G et al. (2017) A Whole-Genome RNA Interference Screen Reveals a Role for Spry2 in Insulin Transcription and the Unfolded Protein Response. Diabetes 66:1703-1712
Ku, Gregory M; Pappalardo, Zachary; Luo, Chun Chieh et al. (2012) An siRNA screen in pancreatic beta cells reveals a role for Gpr27 in insulin production. PLoS Genet 8:e1002449
Ku, Gregory M; Kim, Hail; Vaughn, Ian W et al. (2012) Research resource: RNA-Seq reveals unique features of the pancreatic ?-cell transcriptome. Mol Endocrinol 26:1783-92