During pancreas development cells receive and respond to signals that direct their decisions towards specific lineages. In the past few decades collaborative efforts have allowed us to gain extensive knowledge about pancreas development, islet composition and cell fate specification and function. Furthermore the increasing availability of human pancreas samples have allowed us to explore the similarities and differences between human and mouse pancreas biology. Although this significant progress has improved our understanding of islet cell biology and diabetes we have still not been able to identify mutations that contribute to Type 1 and Type 2 diabetes, suggesting that we are missing some key regulators. One of the most significant findings in genome biology is that most of the genome is transcribed and produces a large variety of non-coding RNAs. One of the non-coding RNA subtypes shown to be important in most aspects of biology are the long noncoding RNAs (lncRNAs) that are characterized by their lack of protein coding potential and length of more than 200 nucleotides. We hypothesize that tissue specific lncRNAs play important roles in specialized cell- specific functions, and that dysregulation of lncRNAs might result in cellular dysfunctions to cause disorders, such as diabetes. We have identified several potential candidate conserved lncRNAs whose expression changes during diabetes. In this proposal we will focus on lncRNA 6330403K07Rik (633), a previously uncharacterized lncRNA that is conserved in mouse and humans, and whose expression increases significantly in multiple mouse models of beta cell dysfunction. Human GWAS studies on diabetic subjects have also identified SNPs in the vicinity of the 633 human ortholog. I will assess expression profile and timeline of 633 upregulation during Type 2 diabetes onset and progression in db/db mice and test the effects of 633 overexpression in beta cells, in vitro and in vivo. Additionally, I will delete 633 in a diabetic mouse model to determine the extent of its contribution to the beta cell dysfunction. This project provides us with a unique opportunity to understand how the upregulation of a lncRNA might impact diabetes onset and progression. The proposed approaches will allow me to identify important molecular mechanisms involved in diabetes progression and has the potential to develop crucial therapeutic targets.

Public Health Relevance

Diabetes is a growing health problem throughout the world and it is critical that we better understand its causes in order to develop better interventions. In this project we propose to investigate a novel regulatory long-noncoding RNAs that is important for disease onset and progression. Specifically, we will focus on lncRNA 6330403K07Rik (633), which we found to be significantly upregulated in several mouse models with beta cell dysfunction and diabetes and has been implicated in human diabetes by GWAS. With this project I will characterize how a novel regulatory molecule influences the onset and/or progression of diabetes and can potentially be an important therapeutic target.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZDK1)
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Castle, Arthur
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University of Colorado Denver
Schools of Medicine
United States
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