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Molecular in vivo imaging of lipid metabolism

English title Molecular in vivo imaging of lipid metabolism
Applicant Dubikovskaya Elena
Number 150134
Funding scheme Project funding (Div. I-III)
Research institution Institut des sciences et ingénierie chimiques EPFL - SB - ISIC
Institution of higher education EPF Lausanne - EPFL
Main discipline Physiology : other topics
Start/End 01.01.2014 - 31.12.2017
Approved amount 449'000.00
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All Disciplines (2)

Discipline
Physiology : other topics
Molecular Biology

Keywords (3)

organic chemistry; lipid metabolism; imaging and quantification

Lay Summary (French)

Lead
Les acides gras sont un métabolite nutritif naturel qui joue un rôle important dans les processus métabolique. Les altérations dans la consommation d'acides gras ont été liées au diabète, aux myopathies cardiaques, à l'hépatostéatose et à la lipotoxicité dans les cellules beta du cœur, du foie et du pancréas. La détection et la quantification des flux d'acides gras sont la clé pour la compréhension des processus métaboliques complexes, impliqués dans toutes les maladies métaboliques.
Lay summary

 

Pour permettre une imagerie quantitative non-invasive en temps réel des flux d'acides gras, nous allons créer une sonde d'imagerie moléculaire qui résumerait avec fidélité l'absorption cellulaire des acides gras et qui pourra être utilisée comme un outil précieux pour localiser et quantifier en temps réel les flux lipidiques. Cette nouvelle approche par l'imagerie devrait favoriser la compréhension des processus physiologiques de base et des altérations pathologiques liés à l'absorption anormale des acides gras et à la diffusion de plusieurs maladies métaboliques.

Direct link to Lay Summary Last update: 24.12.2013

Responsible applicant and co-applicants

Employees

Collaboration

Group / person Country
Types of collaboration
University of California at Berkeley, USA United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
EPFL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Associated projects

Number Title Start Funding scheme
157023 Non-invasive measuring of enzymatic activity and metabolite absorption in living animals using sensitive microsystem 01.11.2014 Interdisciplinary projects

Abstract

Project SummaryThe uptake of lipids such as fatty acids (FFA) is altered under several physiological and pathological conditions reflecting underlying metabolic processes as well as complications, such as fasting, activation of brown adipose tissue (BAT), cardiac hypoxia, and intestinal malabsorption. Excessive uptake of FFAs can also be causal to complications including insulin resistance in skeletal muscle, cardiac myopathies, hepatosteatosis, and lipotoxicity in heart, liver, and pancreatic ß-cells. Further, FFA/lipid fluxes are altered by pharmacological interventions either as part of the drug’s mode of action, as in the case of the anti-diabetic glitazones, which enhance FFA uptake and sequestration by adipocytes, or the anti-obesity compound orlistat, which blocks the generation of FFAs from triglycerides in the intestine, or as an unwanted side effect as exemplified by the anticancer drug doxorubicin causing cardiac metabolic remodeling.Contrary to the initial belief that lipids enter cells through passive diffusion, protein mediated transport systems have been discovered for most naturally occurring lipid groups including fatty acids, cholesterol, and bile acids. Consequently, lipid fluxes can be altered by activation of transporters, mutations in lipid transporter genes, and pharmacological inhibition of transport processes. Thus, localizing and quantifying changes in fatty acid uptake in particular and lipid flux in general has wide implications not only for fundamental biological observations but also for the diagnosis of diseases, the evaluation of novel treatment approaches, and drug discovery in areas ranging from cardiac ischemia, to intestinal malabsorption, and novel BAT based antiobesity treatments. Our overall strategy will be to generate novel fatty acid/lipid imaging compounds based on a lipid-linker-probe design that will enable the molecular imaging of lipid fluxes in vivo based on the uptake specific activation/accumulation of imaging probes for bioluminescent and magnetic resonance imaging. In general, we will synthesize imaging probes, test their uptake, stability, and toxicity in vitro, optimize in vivo delivery methods, and then apply them to animal models of physiological and pathological human processes that are associated with well characterized fatty acid/lipid fluxes such as intestinal lipid absorption and activation of BAT FFA ß-oxidation.
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