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Novel lipid nano-emulsions with superior biological actions: shifting paradigms in current parenteral nutrition

Applicant Hersberger Martin
Number 177225
Funding scheme Sinergia
Research institution Abteilung für Klinische Chemie und Biochemie Kinderspital Universitäts-Kinderkliniken Zürich
Institution of higher education University of Zurich - ZH
Main discipline Interdisciplinary
Start/End 01.05.2018 - 30.04.2022
Approved amount 3'025'858.00
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All Disciplines (3)

Discipline
Interdisciplinary
Pharmacology, Pharmacy
Internal Medicine

Keywords (7)

metabolism; epithelia integrity; inflammation; parenteral nutrition; liver toxicity; gut microbiome; insulin resistance

Lay Summary (German)

Lead
Fette spielen eine wichtige Rolle bei der parenteralen Ernährung, wenn Patienten keine Nahrung oral zu sich nehmen können. Diese parenterale Ernährung rettet Menschenleben und wird jährlich Millionen von Patienten verabreicht. Doch kann die parenterale Ernährung auch Entzündungen auslösen und negative Auswirkungen auf Leber, Darm und den Metabolismus im ganzen Körper, insbesondere auch des Herzens, haben. Bisher verwendete Fettemulsionen zur parenteralen Ernährung sind ausserdem nicht besonders umweltverträglich.
Lay summary

Inhalt und Ziele des Forschungsprojekts

In diesem Projekt werden wir neue Fettemulsionen zur parenteralen Ernährung herstellen und deren Zusammensetzung und Applikationsform so verändern, dass unsere „Designer Emulsionen“ ein optimales „individualisiertes“ Wirkungsprofil aufweisen und umweltverträglicher sind. Dafür werden wir biologische Systeme entwickeln, in denen wir die Wirkungen der parenteralen Ernährung quantifizieren und deren molekulare Mechanismen untersuchen. Diese Modellsysteme werden wir anschliessend zur Bestimmung der biologischen Wirkungen und Nebenwirkungen unserer „Designer Emulsionen“ nutzen.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Wir haben zum Ziel, dass die neu entwickelten „Designer Emulsionen“ ein optimales biologisches Wirkungsprofil aufweisen und deshalb die parenterale Ernährung besser verträglich machen. Wir erwarten, dass die Verwendung der neuen „Designer Emulsionen“ in der Humanmedizin zu einer Verminderung der Morbidität und Mortalität bei Patienten und gleichzeitig zu Einsparungen bei den Gesundheitskosten führen wird. Zudem werden wir neue molekulare Mechanismen zur Wirkung von Fetten auf die Entzündung, die Leber- und Darmfunktion, den Metabolismus des Herzens und des ganzen Körpers untersuchen. Damit werden wir generell zum besseren Verständnis ernährungsbedingter Einflüsse auf unser Wohlbefinden und unsere Gesundheit beitragen.
Direct link to Lay Summary Last update: 04.04.2018

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Abstract

BACKGROUND: Triglyceride (TG)-based lipid emulsions form an integral part of life-saving total parenteral nutrition (TPN) and are provided to millions of patients (up to 5% of all hospitalized patients) who are unable to orally ingest or digest/absorb the necessary daily amount of food. Although lipid emulsions are essential components of TPN because of their dense supply of calories and provision of essential fatty acids, currently available therapies often cause considerable side-effects (inflammation and immunosuppression, liver toxicity, changes in the gut microbiome with loss of epithelial integrity and increased risk of sepsis, metabolic derangements with insulin resistance, and depression of cardiac function). Lipid emulsions based on fish oil, containing high amounts of w-3 polyunsaturated fatty acids, appear to have less side-effects, but are unsustainable (due to ocean overfishing) and risky (due to accumulation of environmental toxins in the food chain). Hence, there is a clear need for further research in parenteral nutrition to improve drug safety. One area in greatest need for immediate attention in research on parenteral nutrition is (as recently stated by the American Society of Parenteral and Enteral Nutrition, ASPEN) “the development of alternate products or methods of delivery of nutrients that are safe (with reduced toxicity) and effective.” HYPOTHESIS: We hypothesize that by modifying lipid droplet size, composition of fatty acids in triglycerides, and emulsifiers, we will be able to create novel lipid emulsions with reliable physicochemical stability, favorable pharmacokinetics, and superior biological actions with less toxicity compared to conventional lipid emulsions.EXPERIMENTAL APPROACH: Scientific questions will be addressed using complementary experiments and models. Because the mouse is an affordable animal model specifically suitable for screening purposes, and enables the use of genetically engineered animals, mice instrumented for intravenous delivery will be used for all in vivo experiments. Standard procedures will be followed to develop the novel lipid emulsions. Pharmacokinetics will be assessed using radioactive tracers and PET imaging. To assess the impact of the novel emulsions on bowel inflammation, models of induced (by dextran sulfate sodium) and spontaneous (IL-10- and Muc-2-deficient mice) bowel inflammation will be used. Effects of TPN on liver inflammation and on whole body insulin sensitivity will be determined. Effects of lipid emulsions on cardiac function will be assessed by echocardiography and by measuring beat-to-beat intracellular Ca2+ transients in isolated working mouse hearts. Elaborated mass spectrometry including GC-MS, UPLC/MRM-MS, and MALDI MS tissue imaging will be used to determine lipid mediators and intermediates.SIGNIFICANCE: Our integrated research project has the potential to shift paradigms in current TPN practice. Novel lipid emulsions for TPN with favorable anti-inflammatory actions and beneficial whole-body metabolic effects will ultimately reduce complication rates (morbidity and mortality) in patients and help to minimize health care costs associated with TPN. We will investigate the effects of intravenous lipid emulsions on the gut microbiome and intestine epithelial integrity, a novel and uncharted area of research. Furthermore, we will fabricate lipid emulsions from sustainable sources, which will have a high market potential. The development of novel lipid emulsions with reduced systemic toxicity is of greatest scientific relevance to the whole field of medicine beyond disciplinary boundaries, as these emulsions have the potential to be used for drug delivery in other medical applications.
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