Determining the Role of apoC-III in the Immune System

确定 apoC-III 在免疫系统中的作用

基本信息

批准号：
10623266
负责人：
Alison Bloom Kohan
金额：
$ 46.33万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
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/10623266
关键词：
Acute Adoptive Transfer Albumins Anti-Inflammatory Agents Apolipoproteins C Binding Bioenergetics Biological Cell physiology Cells Cellular Metabolic Process Chylomicrons Clinical Colitis Colon 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 Predisposition Proliferating Radiolabeled Regulatory T-Lymphocyte Resistance Resolution Respiration Role Source Symptoms T cell response T cell therapy T-Cell Proliferation T-Lymphocyte Testing Therapeutic Therapeutic Uses Tissues Triglycerides apolipoprotein C-III associated symptom delivery vehicle dextran sulfate sodium induced colitis effector T cell extracellular gut inflammation human model in vivo inhibitor interest intestinal homeostasis lipid metabolism lipoprotein lipase metabolic abnormality assessment murine colitis novel therapeutic intervention novel therapeutics overexpression programs receptor response restraint tool translational impact uptake

项目摘要

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 CD4+CD25+Foxp3+ 调节性 T 细胞 (Treg) 是解决肠道炎症的强大工具，并且它们分泌的 IL-10 对于炎症性肠病 (IBD) 的缓解至关重要，但仍存在重大差距确定肠道中增加 Tregs 的机制。我们现在已经确定了实现这一目标的新候选机制：apoC-III 抑制 Tregs 中的脂质摄取。我们的初步数据表明，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 Tregs 的脂质摄取和代谢，从而导致肠道耐受性增加。我们将在 2 个具体目标中检验这一假设：具体目标 1 将检验以下假设：apoC-III 抑制肠道 Tregs 中的脂肪酸摄取，迫使 Tregs 利用替代途径来促进氧化磷酸化，并且这种代谢转变会刺激 Treg 增殖。肠道。我们还将确定 apoC-III 抑制脂质摄取的受体介导机制。具体目标 2 将测试这种 Treg 刺激机制是否可用于治疗两种小鼠结肠炎模型。我们将使用多种方法来提高血浆 apoC-III 水平，并且我们还将抑制 Tregs 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细胞介导的人类结肠炎）。这些研究将确定肠道中 apoC-III 和 Tregs 脂质摄取的极其重要的稳态功能，并将确定通过 apoC-III 刺激肠道 Tregs 来保护治疗性结肠炎的机制。鉴于人们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为 IBD 患者开出这些抑制剂产生重大转化影响。此外，这些研究可能会确定新的治疗策略来提高肠道驻留性、耐受性 Tregs，然后将其用于对现有治疗方法耐药的大部分 IBD 患者 (~30%)。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

T cell cholesterol efflux suppresses apoptosis and senescence and increases atherosclerosis in middle aged mice.

DOI：
10.1038/s41467-022-31135-4
发表时间：
2022-07-01
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Bazioti, Venetia;La Rose, Anouk M.;Maassen, Sjors;Bianchi, Frans;de Boer, Rinse;Halmos, Benedek;Dabral, Deepti;Guilbaud, Emma;Flohr-Svendsen, Arthur;Groenen, Anouk G.;Marmolejo-Garza, Alejandro;Koster, Mirjam H.;Kloosterhuis, Niels J.;Havinga, Rick;Pranger, Alle T.;Langelaar-Makkinje, Miriam;de Bruin, Alain;van de Sluis, Bart;Kohan, Alison B.;Yvan-Charvet, Laurent;van den Bogaart, Geert;Westerterp, Marit
通讯作者：
Westerterp, Marit

The Isolation of Flowing Mesenteric Lymph in Mice to Quantify In Vivo Kinetics of Dietary Lipid Absorption and Chylomicron Secretion.

分离小鼠肠系膜淋巴液以量化膳食脂质吸收和乳糜微粒分泌的体内动力学。