Lineage reprogramming, whereby cells of adult organs are converted from one specialized cell type into another, has emerged in recent years as a promising approach to regenerate cells lost due to disease or injury. This regenerative approach could prove valuable for the treatment of Type 1 diabetes where insulin secreting ?-cells are destroyed by autoimmune attacks. The long-term goal of this proposal is to devise strategies to reprogram adult cells of endodermal organs into pancreatic ?-cells for cell replacement therapies. In a recent study, our research groups showed that pancreatic exocrine cells can be reprogrammed into insulin secreting ?-cells in adult animals by a combination of three transcription factors. We propose to expand on this study and build a set of new tools to investigate the mechanisms of reprogramming and study the reprogramming of several related endodermal cell types, including pancreatic exocrine cells, liver cells and intestine cells, into ?-cells.
In Specific Aim I, we will develop a new generation of viral vectors to dissect the molecular and epigenetic mechanisms of in vivo reprogramming of exocrine cells into ?-cells.
In Specific Aim II, we will develop inducible mouse genetic models to investigate the in vivo reprogramming of adult endodermal cells to ?-cells.
In Specific Aim III, we will use chemical and genetic screens to reprogram hepatocytes to ?-cells ex vivo. Together, these studies are expected to yield important insights into the mechanism of ?-cell reprogramming and help define additional cell types and reprogramming methodologies to regenerate ?-cells in the adult. Such tools and knowledge will form the foundation for developing novel cell replacement therapies for Type 1 diabetes.

Public Health Relevance

Our proposed studies are broadly aimed at developing novel cell replacement therapies for pancreatic ?-cells in order to treat type 1 diabetes. Specifically, we will develop new research tools to define the cell types and conditions whereby cells of pancreas, liver, and intestine can be converted into functional ?-cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK089536-05
Application #
8717645
Study Section
Special Emphasis Panel (ZDK1-GRB-G (M3))
Program Officer
Sato, Sheryl M
Project Start
2010-09-15
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
5
Fiscal Year
2014
Total Cost
$100,000
Indirect Cost
$40,476
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138
Cronican, James J; Beier, Kevin T; Davis, Tina N et al. (2011) A class of human proteins that deliver functional proteins into mammalian cells in vitro and in vivo. Chem Biol 18:833-8