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Elucidation of MicroRNAs as Regulators of Metabolism and Targets for Therapeutic Intervention

Objective

Small RNA-mediated regulation of gene expression is a recent addition to fundamental gene regulatory mechanisms that directly or indirectly affect possibly every gene of a eukaryotic genome. The predominant sources of small RNA in somatic tissues are microRNA genes that encode short dsRNA hairpins of evolutionary conserved sequence. Disorders of metabolism, such as obesity and type 2 diabetes are poorly understood at a molecular level. In this application we propose to explore if miRNA regulatory networks play a role in these diseases. We will employ state of the art methods for identification of small RNAs and their regulated targets and use biochemical, cell and animal model systems to study the detailed molecular mechanisms of metabolic gene regulation by miRNAs. In addition, we will investigate the underlying principles of how RNAs are taken up by cells and develop methods that will improve delivery of miRNA mimetics or inhibitors through cell-specific uptake. The specific aims of this study are: Aim 1: To define the small regulatory miRNA content of liver, muscle and adipose tissue that are associated with abnormal glucose and lipid homeostasis and to dissect the underlying molecular pathways that govern their expression. Aim 2: To characterize the functions of miRNAs in insulin resistance, glucose uptake and production, fatty acid oxidation and lipogenesis. Aim 3: To identify factors and dissect the pathways that regulate RNA uptake by cells and to develop novel pharmacological treatment strategies to manipulate miRNA-expression. Together, this proposal will shed light on the function that miRNA regulatory networks play in metabolism and in the pathophysiology of obesity/type 2 diabetes. In addition, these studies will contribute to the development of new RNA delivery technologies that are urgently needed as experimental tools as well as for novel therapeutic strategies.

Field of science

  • /medical and health sciences/clinical medicine/endocrinology/diabetes
  • /natural sciences/biological sciences/genetics and heredity/rna
  • /natural sciences/biological sciences/biochemistry/biomolecules/lipids

Call for proposal

ERC-2009-AdG
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Funding Scheme

ERC-AG - ERC Advanced Grant

Host institution

EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Address
Raemistrasse 101
8092 Zuerich
Switzerland
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 2 021 235
Principal investigator
Markus Stoffel (Prof.)
Administrative Contact
Markus Stoffel (Prof.)

Beneficiaries (1)

EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Switzerland
EU contribution
€ 2 021 235
Address
Raemistrasse 101
8092 Zuerich
Activity type
Higher or Secondary Education Establishments
Principal investigator
Markus Stoffel (Prof.)
Administrative Contact
Markus Stoffel (Prof.)