The Role of Macrophage Scavenger Receptor 1 in Type 2 Diabetes

摘要 2型糖尿病（T2 D）是一种代谢性疾病，其特征在于胰岛素抵抗、高血糖和脂肪代谢。 组织功能障碍，不成比例地影响非洲裔美国人。肥胖是头号 这是T2 D的一个可改变的风险因素，但将两者联系起来的机制仍不完全清楚。先前 对这一联系的研究表明，肥胖引起慢性炎症状态， 脂肪组织巨噬细胞和炎性细胞因子增加。脂肪组织巨噬细胞 导致脂肪细胞功能障碍和全身性胰岛素抵抗。在我们的理解中， ATM功能如何受肥胖调节并导致脂肪细胞功能障碍。这项提案的目的是 完成以调节与T2 D相关的ATM功能的新机制为中心的研究计划， 加强免疫代谢和转化研究的博士前培训。的中心假设 该建议是巨噬细胞清道夫受体1（MSR 1）是促进胰岛素抵抗所必需的， 脂肪组织炎症通过ATM增殖的调节。MSR 1是多功能巨噬细胞 与人类T2 D相关的表面受体，但也被认为具有保护作用 胰岛素抵抗的影响。我们研究的前提是基于实验室的初步数据， 在Msr 1-/-小鼠中改变ATM增殖。拟议的研究计划将达到以下目的：1） 评估肥胖患者维持胰岛素敏感性对MSR 1的需求，2）评估是否需要MSR 1 3）评估MSR 1在人脂肪组织中的表达，并评估非裔美国人的 T2 D中脂肪组织转录组学。拟议的实验方法将利用肥胖小鼠模型 以及来自肥胖患者的人脂肪组织，结合先进的细胞分选和细胞培养技术， 新陈代谢.研究和培训计划将由赞助商和具有以下专业知识的导师监督： 脂肪组织生物学、免疫代谢、巨噬细胞功能和人体研究。

ABSTRACT Type 2 Diabetes (T2D) is a metabolic disease characterized by insulin resistance, hyperglycemia, and adipose tissue dysfunction that disproportionately affects the African American population. Obesity is the number one modifiable risk factor for T2D, but the mechanisms that link the two remain incompletely understood. Previous research into this link revealed that obesity induces a chronic inflammatory state accompanied by both an increase in adipose tissue macrophages and inflammatory cytokines. Adipose tissue macrophages (ATMs) contribute to adipocyte dysfunction and systemic insulin resistance. Many gaps remain in our understanding of how ATM function is regulated by obesity and contributes to adipocyte dysfunction. The goal of this proposal is to complete a research plan centered on a novel mechanism regulating ATM function relevant to T2D, while enhancing pre-doctoral training in immunometabolism and translational research. The central hypothesis of this proposal is that macrophage scavenger receptor 1 (MSR1) is required to promote insulin resistance and adipose tissue inflammation via the regulation of ATM proliferation. MSR1 is a multifunctional macrophage surface receptor that is associated with T2D in humans but has also been suggested to have protective effects on insulin resistance in mice. The premise for our studies is based on preliminary data in the lab suggesting altered ATM proliferation in Msr1-/- mice. The proposed research plan will address the following aims: 1) To evaluate the requirement for MSR1 maintaining insulin sensitivity in obesity, 2) To evaluate if MSR1 is required for ATM proliferation, 3) To assess MSR1 expression in human adipose tissue and evaluate African American adipose tissue transcriptomics in T2D. The proposed experimental approach will utilize obese mouse models and human adipose tissue from obese patients combined with advanced techniques for cell sorting and cellular metabolism. The research and training plan will be overseen by sponsors and mentors with expertise in adipose tissue biology, immunometabolism, macrophage function, and human subjects research.