Cellular reprogramming has emerged in recent years as a promising approach in regenerative medicine whereby abundant adult cells ofthe body are converted into medically important cell types to repair tissues lost due to disease or injury. This approach could prove valuable for developing treatments for Type 1 diabetes, a disease that results from autoimmune destruction of insulin secreting beta cells. The long term goal of this proposal is to understand the cellular and molecular mechanisms that control beta cell reprogramming. We will take advantage of a recently developed model system where a small number of transcription factors reprogram adult exocrine cells into beta cells.
In Specific Aim I, we will determine the functional contribution of each reprogramming factor to the beta cell reprogramming process.
In Aim II, we will determine the functional and physical interactions between reprogramming factors and chromatin remodeling genes.
In Aim III, we will determine whether exocrine identity genes act as molecular barriers to beta cell reprogramming. The proposed studies are expected to shed important light on the molecular mechanisms that control beta cell reprogramming. Such molecular insights will allow better control ofthe reprogramming process and aid the development of novel cell replacement therapies to treat Type 1 diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Transition Award (R00)
Project #
5R00DK077445-05
Application #
8131844
Study Section
Special Emphasis Panel (NSS)
Program Officer
Sato, Sheryl M
Project Start
2009-09-15
Project End
2012-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
5
Fiscal Year
2011
Total Cost
$243,442
Indirect Cost
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
Cavelti-Weder, C; Zumsteg, A; Li, W et al. (2017) Reprogramming of Pancreatic Acinar Cells to Functional Beta Cells by In Vivo Transduction of a Polycistronic Construct Containing Pdx1, Ngn3, MafA in Mice. Curr Protoc Stem Cell Biol 40:4A.10.1-4A.10.12
Ariyachet, Chaiyaboot; Tovaglieri, Alessio; Xiang, Guanjue et al. (2016) Reprogrammed Stomach Tissue as a Renewable Source of Functional ? Cells for Blood Glucose Regulation. Cell Stem Cell 18:410-21
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
Cavelti-Weder, Claudia; Li, Weida; Zumsteg, Adrian et al. (2015) Direct Reprogramming for Pancreatic Beta-Cells Using Key Developmental Genes. Curr Pathobiol Rep 3:57-65
Li, Weida; Nakanishi, Mio; Zumsteg, Adrian et al. (2014) In vivo reprogramming of pancreatic acinar cells to three islet endocrine subtypes. Elife 3:e01846