Title: Investigation of noncoding variation in human pancreatic islets and their developmental precursors. The goal of this research project is to understand the role of genetic variation in non- protein coding, regulatory regions of the genome in human pancreatic islet function and dysfunction. Insulin-secreting cells in the islet are responsible for maintaining normal blood glucose levels. Type 2 diabetes (T2D) results from progressive failure of these cells to secrete insulin in the face of increasing blood glucose levels and is the cause of substantial morbidity and mortality in the United States and worldwide. Development of T2D involves complex interactions between an individual's genes and environment. Genetic association studies have identified approximately 40 regions in the genome that confer risk of developing T2D. The majority of these regions does not contain coding sequence variants, but instead contains non-coding variants. This project uses genome- wide chromatin profiling to identify the critical regulatory elements that contribute to T2D by determining which of the candidate regulatory regions function as enhancers, silencers, or insulators in human islets (Specific Aim 1) and which elements contain variants that alter gene expression in adult human islets (Specific Aim 2) or in pancreatic precursor cells (Specific Aim 3). Completion of these aims will provide detailed functional annotation of enhancer, silencer, and insulator elements, identify key regulatory element-promoter interactions, and identify how T2D-associated and other variants alter their function in human pancreatic precursor or mature islet cells.

Public Health Relevance

Type 2 diabetes (T2D) afflicts 270-285 million people worldwide and is a major risk factor for subsequent vascular and neurologic morbidity including cardiovascular disease, kidney failure, blindness, and peripheral neuropathy. T2D is the consequence of dysfunction and failure of pancreatic islet beta cells in the context of increased insulin resistance and involves complex interactions between an individual's genes and environment. The goal of this research project is to understand the role(s) of regulatory, non-protein coding regions in human pancreatic islet dysfunction and genetic risk of T2D.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Transition Award (R00)
Project #
4R00DK092251-03
Application #
8827485
Study Section
Special Emphasis Panel (NSS)
Program Officer
Appel, Michael C
Project Start
2014-08-20
Project End
2017-07-31
Budget Start
2014-08-20
Budget End
2015-07-31
Support Year
3
Fiscal Year
2014
Total Cost
$249,000
Indirect Cost
$106,714
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
Kulzer, Jennifer R; Stitzel, Michael L; Morken, Mario A et al. (2014) A common functional regulatory variant at a type 2 diabetes locus upregulates ARAP1 expression in the pancreatic beta cell. Am J Hum Genet 94:186-97