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Unique and overlapping functions and CNS sites of action for NK2R and LepR signaling

Project description

Safe appetite control without aversive effects

Obesity and type 2 diabetes have reached pandemic dimensions. The development of incretin-based drugs has improved treatment, but their use is often limited by side effects, necessitating safer appetite-suppressing alternatives. These drugs mimic gut hormones, enhance insulin release and suppress appetite. With the support of the Marie Skłodowska-Curie Actions programme, the LINK2CNS project focuses on the neurokinin 2 receptor (NK2R) which is implicated in the regulation of smooth muscle activity and pain perception. Recent evidence suggests that NK2R activation reduces food intake and body weight without adverse effects. By studying NK2R and its interaction with leptin signalling in the brain, researchers hope to pave the way for more tolerable treatments for obesity and related metabolic diseases.

Objective

Metabolic diseases such as obesity and diabetes rank among the primary causes of mortality worldwide. While new incretin-based drugs have made major inroads into the treatment of these diseases, issues with tolerance (including nausea, vomiting, diarrhea; and gastroparesis leading to delayed gastric emptying) threaten to limit the potential long-term compliance and impact of these medications. Thus, it is highly relevant to identify therapeutic targets that reduce appetite without activating aversive circuits or promoting gastroparesis. Recently, we discovered Neurokinin 2 Receptor (NK2R) as a new pharmacological target for treating obesity. When activated, NK2R improves energy homeostasis by reducing feeding and increasing energy expenditure, resulting in a decrease in body weight via diminished adiposity. Importantly, NK2R agonism controls appetite without activating CNS circuits that induce aversive effects and, unlike incretin-based therapies, can compensate for leptin-controlled feeding in leptin-deficient hyperphagic mice. This suggests that NK2R agonism mimics leptin for the control of feeding and likely engages leptin-regulated neural circuits. During this fellowship, I will define unique and overlapping functions and CNS sites of action for NK2R and Leptin Receptor signaling using proprietary pharmacological NK2R agonists, molecular genetic neuroscience techniques, metabolic phenotyping, and transcriptomics. This will not only expand our understanding of the promising mode-of-action of NK2R agonists but also has the potential to reveal new mechanisms of central homeostatic control that can be exploited pharmacologically for the treatment of cardiometabolic diseases. The combination of the expertise of my host labs and my experience will ensure the successful completion of the fellowship and uniquely positions me as an expert in both peripheral and central control of energy homeostasis and strengthens my transferable skills to start my independent career.

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HORIZON-TMA-MSCA-PF-GF - HORIZON TMA MSCA Postdoctoral Fellowships - Global Fellowships

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(opens in new window) HORIZON-MSCA-2024-PF-01

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Coordinator

KOBENHAVNS UNIVERSITET
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 423 946,08
Address
NORREGADE 10
1165 KOBENHAVN
Denmark

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Region
Danmark Hovedstaden Byen København
Activity type
Higher or Secondary Education Establishments
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Total cost

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