Cytokine and Metabolic Regulation of Adipose-tissue Tregs

脂肪组织 Tregs 的细胞因子和代谢调节

• 批准号: 10366729
• 负责人: Chaoran Li
• 金额: $ 47.03万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10366729
• 关键词: Ablation; Address; Adipose tissue; Adoptive Transfer; Adult; Affect; Antigen Receptors; Body mass index; Cardiovascular Diseases; Cells; Characteristics; Child; Cholesterol; Cholesterol Homeostasis; Chronic; Chronic Disease; Couples; Data; Development; Diet; Environment; Estrogens; FOXP3 gene; Fatty Liver; Female; Gene Expression Profile; Genes; Genetic; Goals; Gonadal Steroid Hormones; Health; High Fat Diet; Homeostasis; Human; IFNAR1 gene; Immune; Inflammation; Insulin Resistance; Interferon Type I; Interferon-alpha; Interferons; Knowledge; Liver diseases; Lymphoid Tissue; Mediating; Metabolic; Metabolic Diseases; Metabolic hormone; Metabolic syndrome; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Omentum; Outcome; Ovarian; Pathway interactions; Phenotype; Population; Postmenopause; Prevalence; Regulation; Regulatory T-Lymphocyte; Risk; Role; Signal Transduction; Supplementation; System; T-Cell Receptor; Thinness; Tissues; Toxic effect; Transcript; Transgenic Mice; Visceral; Woman; base; biochemical tools; cytokine; diet-induced obesity; estrogen disruption; experimental study; fasting glucose; feeding; in vivo; insulin sensitivity; male; men; mevalonate; novel; novel therapeutics; response; sex; systemic inflammatory response; tool; transcriptome; transcriptomics; uptake

PROJECT SUMMARY Over the last few decades, obesity-associated metabolic disorders, including insulin resistance, type-2 diabetes, and cardiovascular diseases, have become a major health burden, affecting up to a quarter of U.S. adults. Chronic, low-grade inflammation of the visceral adipose tissue (VAT), which eventually leads to systemic inflammation, is a major driver of obesity-induced metabolic abnormalities. However, the mechanisms of the initiation and progression of obesity-induced inflammation are still poorly understood. A unique population of Foxp3+ regulatory T cells (Tregs) with a distinct antigen receptor repertoire and transcriptional profile accumulates in VAT of lean male mice and estrogen-deficient female mice, keeps the inflammation in check, and promotes metabolic health. Obesity, however, leads to significant reduction of VAT Tregs and loss of their distinct features, resulting in elevated inflammation and worsened metabolic outcomes. This obesity- induced toxicity severely hinders the development of VAT-Treg-targeted strategies against metabolic disorders. The overall goal of this proposed project is to use novel genetic and biochemical tools to uncover the unique cytokine, metabolic, and sex-hormone-mediated mechanisms that control the homeostasis of VAT Tregs at steady state, and to investigate how disruption of these pathways could contribute to obesity-induced toxicity of VAT Tregs in both males and estrogen-deficient females. By tracing the dynamics and transcriptomic changes of Tregs residing in the epidydimal VAT (eVAT) in a diet-induced obesity model, we identified that the reduction of eVAT Tregs during long-term high-fat-diet (HFD) feeding is associated with induction of a type I IFN signature and a concurrent loss of transcripts involved in the synthesis and uptake of cholesterol. Further experiments showed that eVAT Tregs preferentially depend on cholesterol homeostasis, which is inhibited by obesity-induced type I IFNs. In addition, we identified that VAT Tregs from female mice respond to obesity differently from males in an estrogen-dependent manner. Building on these observations, we will elucidate the mechanisms that control VAT Treg homeostasis and their response to obesity through three specific aims: In Aim 1, we will elucidate the mechanisms by which elevated type I IFNs drive the decline of eVAT Tregs and promote metabolic abnormalities during obesity. In Aim 2, we will determine the specific role of cholesterol homeostasis in eVAT Tregs and how its perturbation contributes to the dysregulation of eVAT Tregs during obesity. In Aim 3, we will elucidate how VAT Tregs respond to obesity in females with disrupted estrogen signaling. These efforts will support our long-term goal to better understand the mechanisms that drive immune dysregulation in obesity-associated chronic diseases.

项目摘要 在过去的几十年中，肥胖相关的代谢障碍，包括胰岛素抵抗，2型 糖尿病和心血管疾病已成为主要的健康负担，影响到美国四分之一 成年人。内脏脂肪组织（VAT）的慢性低级炎症，最终导致 全身性炎症是肥胖引起的代谢异常的主要驱动力。但是，机制 肥胖引起的炎症的起始和进展仍然很少了解。一个独特的 具有独特的抗原受体库和转录的FOXP3+调节T细胞（Tregs）的种群 轮廓积聚在瘦雄性小鼠和缺陷雌激素的雌性小鼠中，使炎症保持在 检查并促进代谢健康。但是，肥胖导致增值税和损失的显着减少 它们的独特特征，导致炎症升高和代谢结果恶化。这个肥胖 - 诱导的毒性严重阻碍了以新陈代谢为目标的增值税策略 疾病。这个拟议项目的总体目标是使用新颖的遗传和生化工具来揭示 控制增值税稳态的独特细胞因子，代谢和性激素介导的机制 Treg处于稳定状态，并研究这些途径的破坏可能导致肥胖症引起的 男性和雌激素缺乏女性的增值税的毒性。通过追踪动力学和转录组 在饮食引起的肥胖模型中居住在附属增值税（EVAT）中的Treg的变化，我们确定 长期高脂饮食（HFD）喂养过程中的EVAT Tregs降低与I型诱导有关 IFN签名以及胆固醇合成和摄取的转录本的同时丧失。更远 实验表明，EVAT TREG优先取决于胆固醇的稳态，这受到了抑制 肥胖引起的I型IFN。此外，我们确定了女小鼠的增值税对肥胖症有反应 以雌激素依赖性方式不同于男性。以这些观察为基础，我们将阐明 控制增值税Treg稳态的机制及其对肥胖的反应通过三个特定目的： 在AIM 1中，我们将阐明I型IFN升高的机制驱动EVAT TREG的下降和 在肥胖期间促进代谢异常。 在AIM 2中，我们将确定胆固醇稳态在evat tregs中的特定作用以及其扰动如何 在肥胖期间导致EVAT TREG的失调。 在AIM 3中，我们将阐明增值税Treg如何应对雌激素信号传导的女性肥胖症的反应。 这些努力将支持我们的长期目标，以更好地了解动力免疫的机制 肥胖相关慢性疾病的失调。