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Insulin-producing Cells
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Naturally occurring insulin-producing cells
The Pro-insulin gene is normally transcribed and translated by the highly specialized pancreatic beta-cells. This tissue-specific expression of insulin is known to be tightly regulated at the transcriptional as well as post-transcriptional level, by a large range of pancreas-specific (pro-endocrine) transcription factors and regulatory molecules that control pro-insulin gene transcription. The thymus is the other known tissue to produce/present insulin in early life and thymus-specific depletion of Aire-dependent insulin transcription is known to induce autoimmune diabetes. In addition to these two well-known insulin-producing tissues, few reports have demonstrated the occurrance of pro-insulin gene transcripts and protein in different diabetic mouse and rat models, including streptozotocin-treated mice and rats, ob/ob mice, and mice fed high-fat diets.
We are interested in capturing the diversity of non-coding(nc)RNAs, especially microRNAs in human tissues that naturally express varying levels of pro-insulin and other pro-endocrine pancreatic gene transcripts. Over the past years, we identified pro-insulin transcripts in the human brain and gallbladder epithelial cells and are assessing a continually growing biobank of human tissues (shown in the figure above) to create a database of human tissue-specific pro-endocrine transcript and microRNA expression.
A microRNA atlas of insulin-producing cells
As shown above, these three different studies emphasize the role of microRNA processing in pancreatic insulin-producing islet beta cells. It is intriguing that knocking down dicer in islet beta cells can significantly inhibit pro-insulin gene transcript to ~10% of normal levels. These and other studies converge on the idea that multiple specific microRNAs regulate the expression of insulin (and other pro-endocrine) gene transcripts in the endocrine pancreatic islet cells.
With our experience in identifying naturally-occurring insulin producing cells in
a biobank of ~700 different human cells/tissue samples and our expertise in miRNA expression analyses, we aim to
(i) profile miRNA and pro-endocrine gene transcripts in a biobank of ~700 different human cell/tissue samples;
(ii) identify miRNAs that are highly associated with insulin and other pro-endocrine pancreatic transcription factors;
(iii) use multiple biostatistical and machine-learning algorithms to identify a key set of microRNAs that promote insulin-gene transcription;
(iv) use dox-regulatable lentiviral vectors to generate miRNA-over-expression lines using human pancreatic islet and duct cell types;
(v) identify a combination of miRNAs that induce/promote the differentiation to insulin-producing (islet-like) endocrine pancreatic cells.
Our previous studies supported by the research funded through the Department of Biotechnology, Government of India, UK-India Educational Research Initiative (UKIERI), Australian Research Council (ARC) and the JDRF Australia grants to Prof. Anand Hardikar.
Team members
Wilson Wong (Project co-lead), Mugdha Joglekar (Project co-lead), Vijit Saini , Andrzej S. Januszewski, Guozhi Jiang, Grzegorz J. Maciag, Dario Gerace, Sarang N. Satoor, Asma S Ahmed, Ryan J. Farr, Cody Lee-Maynard, David Liuwantara, Tejaswini Sharangdhar, Yi Vee Chew, Subhshri Sahu, Dana AlRijjal, Edwin Lim, Julie Hunter, Anja E. Sorensen, Ammira S. Akil, Khalid Fakhro, Jennifer R. Gamble, Thomas Loudovaris, Thomas W.H. Kay, Helen E. Thomas, Philip O’Connell, Gilles Guillemin, David Martin, David Tosh, Ann M. Simpson, Anthony C. Keech, Louise T. Dalgaard, Ronald C. Ma, Wayne J. Hawthorne.
Present and past funders/supporters: DBT project grant, UKERI / British Council exchange program, ARC Future Fellowship, DART general grant, NHMRC project grant and JDRF Australia Fellowships (to AAH and MVJ), Danish Diabetes Academy, Rebecca L Cooper Foundation, University of Sydney.
