In alignment with Beta Cell Biology Consortium (BCBC) research priorities, we have assembled a strong multidisciplinary team of established investigators to identify epigenetic and genetic programs underlying human pancreatic (-cell development, growth, maturation, function, and fate control. Growth of knowledge about human pancreas and islet developmental biology will accelerate creation of cell therapies for diabetes mellitus, and we propose studies here with an experimental focus on fetal, juvenile and adult human (-cells. For these studies, our team has created and shared new reagents and experimental methods, including human and mouse genetic tools, procurement of human islets with ongoing physiological (-cell proliferation, cell purification strategies, and genome-scale molecular profiling. We will use these and other innovative resources to investigate promising mechanisms for generating functional (-cells, including derivation from multipotent human stem cells, cell reprogramming, and expansion of existing (-cells. In Project 1, we will combine the power of advanced mouse genetics, cell purification, and genomics to elucidate genetic and epigenetic mechanisms controlling development and fates of islet (-cells and other pancreatic cell subsets. These studies should establish genetic and epigenetic foundations for directing controlled cell reprogramming to regenerate (-cells. In Project 2, we will investigate the genetic and epigenetic basis for human pancreatic and islet cell development and maturation, by purifying defined cell subsets from fetal and juvenile human pancreata and applying 'ultrahigh'throughput genomic-scale studies of gene expression and chromatin. In Project 3, we will create new human induced pluripotent stem (iPS) cell lines harboring mutations in genes encoding crucial regulators of pancreatic (-cell development, maturation, and function. These iPS cell lines will provide a unique experimental platform to reveal fundamental genetic and epigenetic mechanisms controlling human islet (-cell development, fate and function. Data sharing, hypotheses, and collaborations fostered in the BCBC through our studies should speed progress toward meeting the BCBC mandate to discover cellular therapies for diabetes mellitus.

Public Health Relevance

In alignment with stated Beta Cell Biology Consortium priorities, our team of investigators proposes to identify the molecular programs underlying human pancreatic islet development, growth, maturation and function to accelerate progress toward cell therapies for diabetes mellitus. We will investigate promising mechanisms for generating functional beta cells, including derivation from multipotent human stem cells, reprogramming of other pancreatic cells, and expansion of existing beta 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 #
5U01DK089532-05
Application #
8717644
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
$26,855
Name
Stanford University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Arda, H Efsun; Benitez, Cecil M; Kim, Seung K (2013) Gene regulatory networks governing pancreas development. Dev Cell 25:5-13
Chen, Hainan; Gu, Xueying; Liu, Yinghua et al. (2011) PDGF signalling controls age-dependent proliferation in pancreatic ?-cells. Nature 478:349-55
Dhawan, Sangeeta; Georgia, Senta; Tschen, Shuen-Ing et al. (2011) Pancreatic ? cell identity is maintained by DNA methylation-mediated repression of Arx. Dev Cell 20:419-29