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Metabolic characteristics of lymphocytes in diabetic rats goto-kakizaki and wistar obese rats with Walker Tumor 256

Grant number: 23/12318-7
Support Opportunities:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): March 01, 2024
Effective date (End): February 29, 2028
Field of knowledge:Biological Sciences - Immunology
Principal Investigator:Renata Gorjao
Grantee:Maria Janaina Leite de Araújo
Host Institution: Pró-Reitoria de Pós-Graduação e Pesquisa. Universidade Cruzeiro do Sul (UNICSUL). São Paulo , SP, Brazil

Abstract

Lymphocytes undergo metabolic reprogramming in inflammatory conditions generated by chronic, systemic, and metabolic diseases, in an attempt to offer an effective immune response to the body. In the tumor environment, cancer cells compete with lymphocytes for glucose and glutamine, suppressing the energy supply of T cells and impairing their effector function. The metabolic reprogramming that occurs with lymphocytes in conditions of obesity or type 2 diabetes mellitus can impair their immune response to tumors, generating increased tumor progression in the presence of these comorbidities. Thus, this study aims to evaluate the metabolic profile of lymphocytes during the progression of Walker 256 tumor in obese Wistar rats, compared to Goto-Kakizaki (GK) rats, a type 2 diabetes experimental model without obesity. Initially, 6-week-old Wistar and GK animals will be divided into 6 groups: 2 groups of GK rats, which will receive a balanced diet, and 2 groups of Wistar rats that will receive a high-fat and high-saccharide diet to induce obesity, and 2 that will receive a balanced diet (control). Subsequently, we will perform the inoculation of tumor cells (Walker 256). We will evaluate tumor progression in lean GK, obese, and non-obese Wistar animals (n=8) for 12 days. The analysis of the tumor volume will be performed, followed by euthanasia. Subsequently, tumor tissue, plasma, and mesenteric lymph nodes will be collected and evaluated: concentration of insulin, leptin, and adiponectin in plasma by ELISA; cytokine concentration in tumor tissue by flow cytometry; lactate production and glucose uptake in lymphocytes maintained in culture in the presence and absence of stimulus; evaluation of enzyme activity related to glycolytic and oxidative metabolism in lymphocytes by spectrophotometry; evaluation of expression of genes involved in metabolism by real-time PCR and analysis of basal oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) using Seahorse. In the present study, we will be able to show that the metabolism of lymphocytes can be an important target to understand the changes in the function of these cells and how they answer to inflammatory stimuli associated with type 2 diabetes mellitus to favor tumor progression. (AU)

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