Determining the Role of apoC-III in the Immune System

虽然我们知道CD4+CD25+Foxp3+调节性T细胞（Tregs）是解决肠道炎症的有力工具，并且它们分泌IL-10对炎症性肠病（IBD）缓解至关重要，但在确定肠道中增加Tregs的机制方面存在重大差距。我们现在已经确定了一种新的候选机制来实现这一目标：apoC-III抑制Tregs的脂质摄取。我们的初步数据显示，apoC-III可以预防IBD，而apoC-III的缺失则是有害的。我们假设apoC-III的一个关键功能是调节肠道treg的脂质摄取和代谢，从而增加肠道的耐受性。我们将在2中验证这一假设：特异性目的1将验证apoC-III抑制脂肪酸进入肠道Treg的假设，迫使Treg利用替代途径来促进氧化磷酸化，并且这种代谢转换刺激了Treg在肠道中的增殖。我们还将确定apoC-III抑制脂质摄取的受体介导机制。特异性目的2将测试Treg刺激的这种机制是否可以用于治疗2种小鼠结肠炎模型。我们将使用多种方法来提高血浆apoC-III水平，我们还将抑制Tregs中的脂质摄取，以确定这是否足以保护rag1 -/-小鼠免受T细胞转移介导的结肠炎（一种与效应T细胞介导的人类结肠炎最相似的模型）。这些研究将确定apoC-III和肠道treg脂质摄取的一个至关重要的稳态功能，并将确定通过apoC-III刺激肠道treg治疗性结肠炎的保护机制。鉴于对通过反义抑制剂抑制apoC-III的兴趣，这些研究的结果将对如何给IBD患者开这些抑制剂有重大的转化影响。此外，这些研究可能确定新的治疗策略，以提高肠道内的耐受性Tregs，然后可用于对现有治疗方法有耐药性的IBD患者的大部分（约30%）。

While we know that CD4+CD25+Foxp3+ regulatory T cells (Tregs) are a powerful tool in the resolution of gut inflammation, and that their secretion of IL-10 is critical to inflammatory bowel disease (IBD) remission, there is a major gap in identifying mechanisms for increasing Tregs in the intestine. We have now identified a new candidate mechanism to achieve this goal: apoC-III inhibition of lipid uptake in Tregs. Our preliminary data shows that apoC-III protects from IBD, whereas loss of apoC-III is detrimental. We hypothesize that a critical function of apoC-III is to regulate lipid uptake and metabolism in intestinal Tregs, which results in increased tolerogenicity in the gut. We will test this hypothesis in 2 Specific Aims: Specific aim 1 will test the hypothesis that apoC-III inhibits fatty acid uptake into intestinal Tregs, forcing Tregs to utilize alternative pathways to fuel oxidative phosphorylation, and that this switch in metabolism stimulates Treg proliferation in the intestine. We will also identify receptor-mediated mechanisms by which apoC-III inhibits lipid uptake. Specific Aim 2 will test whether this mechanism of Treg stimulation can be used therapeutically in 2 models of murine colitis. We will use multiple approaches to raise plasma apoC-III levels, and we will also inhibit lipid uptake in Tregs to identify whether this is sufficient to protect RAG-1-/- mice from T cell transfer-mediated colitis (a model most similar to the effector T cell mediated human colitis). These studies will define a critically important homeostatic function for apoC-III and lipid uptake by Tregs in the gut, and will determine the mechanism of therapeutic colitis protection via apoC-III stimulation of intestinal Tregs. Given the interest in inhibiting apoC-III via antisense inhibitors, the outcome of these studies will have a significant translational impact on how these inhibitors are prescribed to patients with IBD. Additionally, these studies may identify novel therapeutic strategies to raising intestinally resident, tolerogenic Tregs which could then be used in the large proportion of IBD patients (~30%) who are resistant to existing therapeutic approaches.