The Role of Macrophage Scavenger Receptor 1 in Type 2 Diabetes

摘要 2型糖尿病是一种以胰岛素抵抗、高血糖和脂肪为特征的代谢性疾病 组织功能障碍对非裔美国人的影响不成比例。肥胖是第一位的 T2D的危险因素是可修改的，但将两者联系起来的机制仍不完全清楚。上一首 对这一联系的研究表明，肥胖会导致慢性炎症状态，同时伴随着 脂肪组织中巨噬细胞和炎性细胞因子增多。脂肪组织巨噬细胞(ATM) 导致脂肪细胞功能障碍和全身性胰岛素抵抗。在我们对……的理解上仍然存在许多差距 ATM功能如何受到肥胖的调节，并导致脂肪细胞功能障碍。这项提议的目标是 完成一项研究计划，以监管与T2D相关的ATM功能的新机制为中心，同时 加强免疫代谢和翻译研究方面的博士前培训。的中心假说 这一建议是巨噬细胞清道夫受体1(MSR1)需要促进胰岛素抵抗和 脂肪组织炎症通过调节ATM的增殖来实现。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 对小鼠的胰岛素抵抗。我们研究的前提是基于实验室的初步数据 改变Msr1-/-小鼠的ATM增殖。拟议的研究计划将涉及以下目标：1) 评估肥胖患者对MSR1维持胰岛素敏感性的需求，2)评估是否需要MSR1 对于ATM增殖，3)评估MSR1在人类脂肪组织中的表达，并评估非裔美国人 T2D中的脂肪组织转录组。建议的实验方法将利用肥胖的小鼠模型。 和肥胖症患者的人类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.