Determining the Role of apoC-III in the Immune System

确定 apoC-III 在免疫系统中的作用

• 批准号: 10205050
• 负责人: Alison Bloom Kohan
• 金额: $ 45.64万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10205050
• 关键词: Acute; Adoptive Transfer; Albumins; Anti-Inflammatory Agents; Apolipoproteins C; Bioenergetics; Biological; Cells; Cellular Metabolic Process; Chylomicrons; Clinical; Colitis; Data; Diffuse; Disease remission; FOXP3 gene; Fatty Acids; Gene Expression; Glucose; Goals; Homeostasis; Homing; Human; Hydrolysis; Hyperlipidemia; IL2RA gene; Immune; Immune system; Inflammatory Bowel Diseases; Interleukin-10; Intestinal Mucosa; Intestines; Laboratories; Lipids; Lipoproteins; Liver; Low Density Lipoprotein Receptor; Mediating; Metabolic; Metabolism; Modeling; Mucosal Immunity; Mucous Membrane; Mus; Outcome; Outcome Study; Oxidative Phosphorylation; Pathway interactions; Patients; Pattern; Physiological; Plasma; Play; Proliferating; Radiolabeled; Regulatory T-Lymphocyte; Resistance; Resolution; Respiration; Role; Source; Symptoms; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic; Therapeutic Uses; Tissues; Treg therapy; Triglycerides; associated symptom; dextran sulfate sodium induced colitis; effector T cell; extracellular; human model; in vivo; inflammatory disease of the intestine; inhibitor/antagonist; interest; intestinal homeostasis; lipid metabolism; lipoprotein lipase; metabolic abnormality assessment; mouse model; novel therapeutic intervention; novel therapeutics; overexpression; programs; receptor; response; tool; translational impact; uptake

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.

虽然我们知道CD 4 + CD 25 + Foxp 3+调节性T细胞（TCRs）是解决肠道炎症的有力工具，并且它们分泌的IL-10对炎症性肠病（IBD）缓解至关重要，但在确定增加肠道TCRs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抑制调节性T细胞的脂质摄入。我们的初步数据表明，apoC-III保护IBD，而apoC-III的损失是有害的。我们假设apoC-III的一个关键功能是调节肠道THP中的脂质摄取和代谢，这导致肠道中耐受性增加。我们将在2个特定目的中检验这一假设：特定目的1将检验以下假设：apoC-III抑制脂肪酸摄取到肠TcR中，迫使TcR利用替代途径来促进氧化磷酸化，并且这种代谢转换刺激肠中Treg增殖。我们还将确定apoC-III抑制脂质摄取的受体介导的机制。具体目标2将测试Treg刺激的这种机制是否可以在2种鼠结肠炎模型中治疗性使用。我们将使用多种方法来提高血浆apoC-III水平，并且我们还将抑制T细胞中的脂质摄取，以确定这是否足以保护RAG-1-/-小鼠免受T细胞转移介导的结肠炎（与效应T细胞介导的人结肠炎最相似的模型）。这些研究将确定apoC-III和肠道中Tcl 3的脂质摄取的至关重要的稳态功能，并将确定通过apoC-III刺激肠道Tcl 3的治疗性结肠炎保护的机制。考虑到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将这些抑制剂处方给IBD患者产生重大的转化影响。此外，这些研究可以确定新的治疗策略，以提高体内驻留的致耐受性TdR，然后可以用于大部分对现有治疗方法具有耐药性的IBD患者（约30%）。