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Metabolic effects of LTB4 in macrophages and systemic inflammation in type 1 diabetic mice

Grant number: 19/22369-2
Support Opportunities:Scholarships abroad - Research Internship - Master's degree
Effective date (Start): March 02, 2020
Effective date (End): September 01, 2020
Field of knowledge:Biological Sciences - Immunology
Principal Investigator:Sônia Jancar
Grantee:Nayara Pereira
Supervisor: Carlos Henrique Cardoso Serezani
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Research place: Vanderbilt University (VU), United States  
Associated to the scholarship:18/10230-7 - Effect of leukotrienes on lipic metabolism in type 1 diabetic mice, BP.MS


Despite aggressive glucose monitoring and insulin therapy, many patients spend large portions of the day in a hyperglycemic state, placing them at risk for the development of comorbidities. Chronic hypoinsulinemia in diabetes drives systemic inflammation that contributes to many comorbidities, including weight loss, dyslipidemia, low grade inflammation and enhanced risk of infection. Our research group and others have shown that the bioactive lipid mediator leukotriene-B4 (LTB4) is a key regulator of the inflammatory response. Works from our research group have shown that LTB4 produced in the context of systemic inflammation contribute to induce dysregulation of systemic lipid metabolism, fatty acid uptake and uncoupling mitochondrial respiration in macrophages. Also, preliminary results have indicated that leukotrienes are involved in adiposity loss in T1D mice, which would reflect the systemic inflammation and activated macrophage phenotype that depends on the metabolic programming related to fatty acid oxidation. Based on this, the purpose of this project is to investigate the involvement of LTB4 specifically on energy imbalance in macrophages and adiposity loss. We will use the streptozotocin-induced hyperglycemia model in LysMcre BLT1fl/fl (BLT1myel) mice to determine if myeloid-specific LTB4 actions dictate metaflammation in diabetes. We are planning to measure the body composition of diabetic and healthy BLT1myel mice, as well as the production of inflammatory mediators from adipose tissue. To evaluate how LTB4 influences the metabolism of macrophages, we will determine the capacity of these cells to exert mitochondrial respiration by oxidative metabolism analyzing their oxygen consumption and mitochondrial dynamics will be evaluated by microscopy imaging. This proposal seeks to define the role of diabetes-induced hypoinsulinemia in promoting immunometabolic mechanisms that dysregulate molecular checkpoints, leading to a detrimental host inflammatory response and favoring inflammatory morbidities associated with uncontrolled diabetes. (AU)

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