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Activation and metabolism status of macrophages in metabolic disease and potential impact of tyrosine kinase inhibitors (TKIs)

Applicant Cavelti-Weder Claudia
Number 161135
Funding scheme Ambizione
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Endocrinology
Start/End 01.09.2015 - 31.08.2018
Approved amount 600'000.00
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All Disciplines (2)

Discipline
Endocrinology
Immunology, Immunopathology

Keywords (4)

Inflammation; Diabetes; Macrophages; Adipositas

Lay Summary (German)

Lead
Typ 2 Diabetes und Übergewicht gehen mit einem Entzündungszustand und vermehrten Makrophagen in verschiedenen Geweben und der Blutbahn einher. Unser Ziel ist die Untersuchung des Aktivierungszustandes und des Glucose-Metabolismus von Makrophagen bei Typ 2 Diabetes und Adipositas und die Beeinflussbarkeit durch Tyrosin Kinase Inhibitoren.
Lay summary

Inhalt und Ziele des Forschungsprojekts:

Das Immunsystem spielt bei Typ 2 Diabetes und Adipositas eine wichtige Rolle. So sind beispielsweise Entzündungsfaktoren und Immunzellen in Anzahl erhöht und deren Aktivierungszustand aktiviert. Es ist jedoch nicht bekannt, ob der Aktivierungszustand von Immunzellen medikamentös beeinflusst werden kann.

Das aktuelle Projekt befasst sich mit der Frage, ob die Medikamenten- Gruppe der Tyrosin Kinase Inhibitoren den Aktivierungszustand und den Glucose- Metabolismus (Verstoffwechselung von Glucose) bei Makrophagen beeinflussen können und dadurch eine Verbesserung bei metabolischen Erkrankungen (Typ 2 Diabetes und Adipositas) erreicht werden kann.

In einer ersten Phase werden wir die Wirkung von Tyrosin Kinase Inhibitoren auf Makrophagen in vitro überprüfen. In einer zweiten Phase werden wir das Medikament in vivo bei einem Typ 2 Diabetes- und einem Adipositas Modell anwenden. Zudem möchten wir auch Blutzellen von Patienten mit Typ 2 Diabetes und Adipositas gewinnen um die Wirkung der Tyrosin Kinase Inhibitoren auf Aktivierungszustand und Glucose- Metabolismus in humanen Zellen in vitro zu überprüfen. Unsere Resultate werden somit die Fragen adressieren, ob der Aktivierungszustand von Immunzellen als möglicher Angriffspunkt einer Therapie von metabolischen Erkrankungen in Frage kommt.

 

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Das Projekt befasst sich mit Grundlagenforschung. Unser langfristiges Ziel ist es, die Rolle von Immunzellen bei Typ 2 Diabetes und Adipositas besser zu verstehen und dadurch gezielte Therapien zu entwickeln, welche gleichzeitig die BZ- Einstellung, die Entzündung und kardiovaskulären Komplikationen beeinflussen können.

Direct link to Lay Summary Last update: 02.09.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
GLP-1 Analogues as a Complementary Therapy in Patients after Metabolic Surgery: a Systematic Review and Qualitative Synthesis
Schneider Romano, Kraljević Marko, Peterli Ralph, Rohm Theresa V., Klasen Jennifer M., Cavelti-Weder Claudia, Delko Tarik (2020), GLP-1 Analogues as a Complementary Therapy in Patients after Metabolic Surgery: a Systematic Review and Qualitative Synthesis, in Obesity Surgery.
Treatment of Primary Aldosteronism With mTORC1 Inhibitors
Trinh Beckey, Hepprich Matthias, Betz Matthias J, Burkard Thilo, Cavelti-Weder Claudia, Seelig Eleonora, Meienberg Fabian, Kratschmar Denise V, Beuschlein Felix, Reincke Martin, Odermatt Alex, Hall Michael N, Donath Marc Y, Swierczynska Marta M (2019), Treatment of Primary Aldosteronism With mTORC1 Inhibitors, in The Journal of Clinical Endocrinology & Metabolism, 104(10), 4703-4714.
Imatinib reduces non-alcoholic fatty liver disease in obese mice by targeting inflammatory and lipogenic pathways in macrophages and liver
AlAsfoorShefaa, RohmTheresa V., BoschAngela J. T., DervosThomas, CalabreseDiego, MatterMatthias S., WeberAchim, Cavelti-WederClaudia, Imatinib reduces non-alcoholic fatty liver disease in obese mice by targeting inflammatory and lipogenic pathways in macrophages and liver, in Scientific Reports - Nature.

Collaboration

Group / person Country
Types of collaboration
Laboratory Prof. Marc Donath, Department Biomedizin Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Laboratory Prof. Christoph Hess, Department Biomedizin Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
ADA 2020 Talk given at a conference Proinflammatory Intestinal Macrophages Are Increased in Obesity Potentially by Enhanced Recruitment of Blood Monocytes 12.06.2020 Chicago, United States of America Cavelti-Weder Claudia;
SGED 2019 Talk given at a conference High fat diet-induced activation of colonic macrophages is linked to glycemic control. 14.11.2019 Bern, Switzerland Cavelti-Weder Claudia;
SGED Poster Air pollution mediates diabetes via oral exposure by disrupting innate mucosal immunity. 01.11.2019 Bern, Switzerland Bosch Angela; Cavelti-Weder Claudia;
ADA 2019 Poster Oral Exposure to Air Pollutants Mediates Diabetes via Innate Immunity. 01.06.2019 San Francisco, United States of America Bosch Angela; Cavelti-Weder Claudia;
UniBasel Immunology Community (UBICO) Poster Air pollution-induced diabetes is mediated via the gastrointestinal tract. 01.03.2019 Engelberg, Switzerland Bosch Angela; Cavelti-Weder Claudia;
SGED 2018 Poster Targeting Intestinal Macrophages as a Potential Therapeutic Option in Metabolic Disease 01.11.2018 Bern, Switzerland Cavelti-Weder Claudia;
ADA 2018 Talk given at a conference Targeting Intestinal Macrophages as a Potential Therapeutic Option in Obesity. 22.06.2018 Orlando, United States of America Cavelti-Weder Claudia;
ADA 2018 Talk given at a conference Targeting intestinal macrophages as a potential therapeutic option in obesity. 01.06.2018 Orlando, United States of America Cavelti-Weder Claudia;
UniBasel Immunology Community (UBICO) Talk given at a conference Phenotypic Switch of Intestinal macrophages in obesity. 01.03.2018 Engelberg, Switzerland Cavelti-Weder Claudia;
SGED 2017 Talk given at a conference Imatinib Exerts Immune-Modulatory Effects on Pro-Inflammatory Macrophages in Metabolic Disease. 16.11.2017 Bern, Switzerland Cavelti-Weder Claudia;
SGED 2018 Talk given at a conference Air pollution-induced diabetes is mediated via the gut. 14.11.2017 Bern, Switzerland Cavelti-Weder Claudia; Bosch Angela;
UniBasel Immunology Community (UBICO) Poster Pharmacological Attenuation of Macrophage Activation by Imatinib Reverts Hepatic Steatosis and Inflammation in Obese Mice. 30.10.2017 Engelberg, Switzerland Cavelti-Weder Claudia;
Life Sciences Symposium “Frontiers of Metabolism” Poster Pharmacological attenuation of macrophage activation by imatinib reverts hepatic steatosis and inflammation in obese mice. 24.10.2017 Lausanne, Switzerland Cavelti-Weder Claudia;
Life Sciences Symposium “Frontiers of Metabolism” Poster Obesity-protected mouse models are protected from HFD-induced increase of inflammatory intestinal macrophages. 24.10.2017 Lausanne, Switzerland Cavelti-Weder Claudia;
UniBasel Immunology Community (UBICO) Talk given at a conference Intestinal Macrophages in Obesity. 20.10.2017 Engelberg, Switzerland Cavelti-Weder Claudia;
ADA 2017 Poster Increased Inflammatory Intestinal Macrophage Subpopulations after High Fat Diet 13.06.2017 San Diego, United States of America Cavelti-Weder Claudia; Bosch Angela;
SGED 2016 Poster Pro-inflammatory macrophages are attenuated by immune-modulatory effects of imatinib 17.11.2016 Bern, Switzerland Bosch Angela; Cavelti-Weder Claudia;
SGED 2016 Talk given at a conference Increased Inflammatory Intestinal Macrophage Subsets after High Fat Diet 13.11.2016 Bern, Switzerland Bosch Angela; Cavelti-Weder Claudia;
UniBasel Immunology Community (UBICO) Talk given at a conference Role of macrophage activation in metabolic disease. 31.10.2016 Engelberg, Switzerland Cavelti-Weder Claudia;
UniBasel Immunology Community (UBICO) Poster Distinct intestinal macrophage subpopulations in metabolic disease. 30.10.2016 Engelberg, Switzerland Cavelti-Weder Claudia;
ADA 2016 Poster Potential role of tyrosine kinase inhibitors on macrophage polarization in metabolic disease 10.06.2016 New Orleans, United States of America Cavelti-Weder Claudia;
SGED 2017 Talk given at a conference Obesity-Protected Mouse Models are protected from HFD-induced Increase of Inflammatory Intestinal Macrophages. 16.11.2015 Bern, Switzerland Cavelti-Weder Claudia;


Awards

Title Year
Swiss Government Excellence Scholarship 2015

Associated projects

Number Title Start Funding scheme
180472 Activation and metabolism status of macrophages in metabolic disease and potential impact of tyrosine kinase inhibitors (TKIs) 01.09.2018 Ambizione

Abstract

Diabetes is a serious and growing health problem. According to the International Diabetes Federation, in 2013 382 million people have been affected worldwide. The main characteristics of type 1 and type 2 diabetes are hyperglycemia resulting from defects in insulin secretion by beta-cells, and insulin resistance by peripheral tissue in type 2 diabetes. In metabolic diseases such as type 2 diabetes and obesity, the detrimental role of inflammation is being increasingly acknowledged: Elevated pro-inflammatory cytokines and increased numbers of activated immune cells have been reported. Typically, activated immune cells use glycolysis instead of oxidative phosphorylation as source of their metabolic energy. By integrating knowledge of activation and metabolism status of immune cells in type 2 diabetes and obesity, a better understanding of disease pathogenesis and potential targets for immunometabolic drugs will be obtained. Our aim is to study the link between the activation and metabolism status of macrophages in obesity and type 2 diabetes and to test whether macrophages’ activation and metabolism status can be altered by treatment with tyrosine kinase inhibitors (TKIs). The ultimate goal is to find tailored immunometabolic treatments capable to improve inflammation, glycemia and long-term cardiovascular complications without adverse effects on immune cells.
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