The Role of Macrophage Scavenger Receptor 1 in Type 2 Diabetes

摘要 2 型糖尿病 (T2D) 是一种以胰岛素抵抗、高血糖和脂肪代谢为特征的代谢性疾病 组织功能障碍对非裔美国人造成了不成比例的影响。肥胖是第一位 T2D 的可改变风险因素，但将两者联系起来的机制仍不完全清楚。上一页 对这种联系的研究表明，肥胖会诱发慢性炎症状态，并伴有 脂肪组织巨噬细胞和炎症细胞因子增加。脂肪组织巨噬细胞 (ATM) 导致脂肪细胞功能障碍和全身胰岛素抵抗。我们的理解仍然存在许多差距 ATM 功能如何受肥胖调节并导致脂肪细胞功能障碍。该提案的目标是 完成一项以调节与 T2D 相关的 ATM 功能的新机制为中心的研究计划，同时 加强免疫代谢和转化研究方面的博士前培训。中心假设为 该提议认为，巨噬细胞清道夫受体 1 (MSR1) 是促进胰岛素抵抗所必需的，并且 通过调节 ATM 增殖来调节脂肪组织炎症。 MSR1是一种多功能巨噬细胞 与人类 T2D 相关的表面受体，但也被认为具有保护作用 对小鼠胰岛素抵抗的影响。我们研究的前提是基于实验室的初步数据表明 改变 Msr1-/- 小鼠的 ATM 增殖。拟议的研究计划将实现以下目标： 1) 评估肥胖患者维持胰岛素敏感性的 MSR1 需求，2) 评估是否需要 MSR1 用于 ATM 增殖，3) 评估人类脂肪组织中的 MSR1 表达并评估非裔美国人 T2D 中的脂肪组织转录组学。所提出的实验方法将利用肥胖小鼠模型 和来自肥胖患者的人体脂肪组织，结合先进的细胞分选和细胞技术 新陈代谢。研究和培训计划将由具有以下专业知识的赞助商和导师监督 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.