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BEDREHELSE-Bedre helse og livskvalitet

Signaling Impairments GeNerated by Endocrine Disruptors.

Tildelt: kr 5,9 mill.

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Endocrine disruptors are chemicals that interfere with the body's endocrine system, thereby generating adverse effects. Recently, we demonstrated that persistent organic pollutants (POPs), which are omnipresent in our environment, could lead to insulin re sistance, a hallmark of type 2 diabetes (T2D) and obesity. The molecular mechanisms behind these harmful effects are currently unknown. SIGNED aims to understand how POPs, but also other endocrine disruptors like bisphenol A, can impair insulin action and affect glucose and lipid metabolism. To resolve this challenging task, this research proposal aims to explore the following questions: 1) Are there specific insulin-sensitive cells primarily affected by environmental pollutants? 2) How do pollutants affe ct insulin action when present as single compounds and as mixtures? 3) What are the dose-response effects of endocrine disruptors? 4) Which signaling pathways contribute to insulin resistance? SIGNED will apply an integrative and multi-tiered approach th at will combine cutting edge molecular techniques with metabolic phenotyping in order to understand how changes at protein and gene levels (phosphorylation, expression, miRNA, epigenetics) can explain changes in metabolic response to environmental polluta nts. First, the in vitro mechanistic modes of action of pollutants as single compounds and mixtures will be deciphered in different insulin sensitive cells. Then, we will transfer our in vitro knowledge to in vivo models, and explore the potential signall ing pathways regulated by endocrine disruptors. Altogether, SIGNED will contribute to discover novel and important cellular and molecular mechanisms by which endocrine disruptors can induce insulin resistance, thereby opening new directions for the preve ntion and treatment of metabolic diseases.

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BEDREHELSE-Bedre helse og livskvalitet