Project details

or


Promoting beta-cell survival in type 1 diabetes

Keywords:
diabetes insulin basic research

Researchers:
dr. J.W. Jonker
dr. J.K. Kruit

Nature of the research:
This is a fundamental research project using various molecular and cell biological techniques aimed to identify novel targets to treat or prevent type 1 diabetes.

Fields of study:
pediatrics medical biology diabetes

Background / introduction
Insulin secretion from pancreatic beta-cells is essential for blood glucose homeostasis. In type 1 diabetes (T1D), pancreatic beta-cells are attacked by the immune system leading to a selective and progressive beta-cell loss. This chronic disease is most prominent amongst young children and requires life-long meticulous glucose monitoring and insulin replacement therapy for survival. Accumulating evidence indicates that the triggering of islet inflammation (“insulitis“) and diabetes depends on a dialogue between invading immune cells and targeted beta-cells. Targeted modulation of this communication might therefore be a novel therapeutic strategy for T1D.
Research question / problem definition
MicroRNAs (miRNAs) are short, endogenous, noncoding RNA that regulate gene expression at a posttranscriptional level. Recent studies have shown that several miRNAs play a potential role in cytokine-induced beta-cell apoptosis. Targeting miRNAs to reduce beta-cell apoptosis could, therefore, be a novel strategy to prevent or treat T1D. Our objective is to determine the potential of miRNA-based therapy to prevent or delay the development of T1D in vivo.
Workplan
Modulation of the microRNA expression will be done using beta-cell gene therapy in model organisms for T1D. The development of diabetes will be followed using several techniques such as in vivo measurements of glucose metabolism and scoring of insulitis and beta-cell apoptosis in the pancreas using immunohistochemistry. Furthermore, microRNA targets will be identifies using in vitro techniques.
References
1) Kruit JK, Wijesekara N, Westwell-Roper C, Vanmierlo T, de Haan W, Bhattacharjee A, Tang R, Wellington CL, LutJohann D, Johnson JD, Brunham LR, Verchere CB, Hayden MR. 2012 Loss of both ABCA1 and ABCG1 results in increased disturbances in islet sterol homeostasis, inflammation, and impaired beta-cell function. Diabetes, 61(3): 659-64.

2) Kruit JK, Wijesekara N, Fox JE, Dai XQ, Brunham LR, Searle GJ, Morgan GP, Costin AJ, Tang R, Bhattacharjee A, Johnson JD, Light PE, Marsh BJ, Macdonald PE, Verchere CB, Hayden MR. 2011 Islet cholesterol accumulation due to loss of ABCA1 leads to impaired exocytosis of insulin granules. Diabetes, 60 (12): 3186-96.
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