Lipid Antigen Presentation as a Driver of T2D Inflammation

脂质抗原呈递作为 T2D 炎症的驱动因素

基本信息

批准号：
10687176
负责人：
Dequina Angelina Nicholas
金额：
$ 46.79万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-18 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10687176
关键词：
3D Print Adipose tissue American Anti-Inflammatory Agents Antibodies Antigen Presentation Antigen-Presenting Cells Antigens Area Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Responses Autoimmunity Automobile Driving B-Lymphocytes B-cell receptor repertoire sequencing Biochemistry Biological Assay Biological Models Blood specimen CD1 Antigens Cell physiology Cells Chronic Color Communities Complement Computer Models Computing Methodologies Coupled Creativeness Custom Development Disease Disease Management Enzyme-Linked Immunosorbent Assay Fatty Acids Fatty acid glycerol esters Flow Cytometry Goals Health High Fat Diet Homeostasis Human Immune Immune response Immune system Immunologics Immunophenotyping In Vitro Inflammation Inflammatory Inflammatory Response Insulin Resistance Investigation Laboratories Left Lipids Mediating Molecular Biology Techniques Mus Nature Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Outcome Pathway interactions Patients Persons Phenotype Postdoctoral Fellow Protein Analysis Protein Engineering Proteins Research Role Sampling Saturated Fatty Acids Serum Systems Biology T cell response T-Cell Activation T-Cell Receptor T-Lymphocyte Testing Therapeutic Transgenic Mice Transgenic Organisms Triglycerides Work cytokine human model humanized mouse immune function in vitro Model in vivo innovation mouse model neutralizing antibody new technology new therapeutic target novel prevent response single-cell RNA sequencing therapeutic development translational potential

项目摘要

PROJECT SUMMARY Substantial research effort has uncovered a critical role for chronic inflammation in the development of insulin resistance, a hallmark of Type 2 Diabetes (T2D). Even with this discovery, no successful anti-inflammatory therapeutics have been developed, and research has stagnated with a focus on characterizing adipose tissue inflammation in mouse models of T2D. Importantly, the initiator of chronic inflammation in T2D remains unknown. Type 2 Diabetes presents with autoantibodies against a wide array of self-proteins, but protein screens for antibody reactivity have not discovered initiators of T2D inflammation. Remarkably, not all autoantigens in T2D are protein. We have identified lipid autoantigens in T2D that have been completely overlooked, likely due to the proteins which present lipid antigen, Group 1 CD1 molecules, not being expressed in mice. This lack of expression has left a gaping hole in our understanding of lipid antigens in immunological homeostasis and disease, especially T2D. To remedy this issue, we will use transgenic mice which express human CD1 molecules and in vitro models of human immune responses to understand lipid-mediated immune function in T2D. The long-term goal of this proposal is to establish a new scientific direction with the broad long-term purpose of understanding the role of lipids in pro-inflammatory responses, T2D, and autoimmune diseases. This proposal tests the overarching hypothesis that lipid antigen presentation is a key mechanism by which chronic inflammation in T2D is initiated. This innovative and novel investigation of lipid antigen presentation in T2D combines use of human blood samples, transgenic and humanized mice, single cell RNA sequencing, multiparameter cytokine analysis and flow cytometry, coupled with computational methods that allow for a systems biology approach to antigen discovery and hypotheses testing. In research Area 1, we will assess lipid antigen dependent activation of T cell responses. We will use humanized mice and human blood samples to interrogate the impact of these lipid antigens on T cell function in vitro (CD1 tetramer loading) and in vivo (high fat diet). In research Area 2, we will target lipid antigen presentation to prevent and treat T2D. The capacity of neutralizing antibodies targeted against group 1 CD1 molecules and lipid autoantigens to inhibit pro-inflammatory cytokines secreted from human immune cells and to prevent and treat disease in transgenic mice will be assessed. In research Area 3. Lipid autoantigen discovery in T2D will be performed with a novel 3D printed lipid microarray for antibody profiling. This proposal has the potential to redefine T2D as an autoimmune disease driven by lipid antigen presentation and completely change the strategies for management of disease and therapeutic development. Outcomes of this proposal will allow for the identification of specific inflammatory pathways that can be targeted for disease treatment.

项目概要大量研究工作揭示了慢性炎症在胰岛素发展中的关键作用抵抗力是 2 型糖尿病 (T2D) 的一个标志。即使有了这一发现，仍然没有成功的抗炎药物治疗方法已经开发出来，但研究却停滞不前，重点是表征脂肪组织 T2D 小鼠模型中的炎症。重要的是，T2D 慢性炎症的引发者仍然是未知。 2 型糖尿病存在针对多种自身蛋白的自身抗体，但蛋白质抗体反应性筛查尚未发现 T2D 炎症的引发剂。值得注意的是，并非所有 T2D 中的自身抗原是蛋白质。我们已经鉴定出 T2D 中的脂质自身抗原，这些抗原已完全被被忽视，可能是由于呈现脂质抗原的蛋白质（第 1 组 CD1 分子）未表达在小鼠中。这种表达的缺乏给我们对免疫学中脂质抗原的理解留下了一个巨大的漏洞。稳态和疾病，尤其是 T2D。为了解决这个问题，我们将使用表达人类 CD1 分子和人类免疫反应的体外模型，以了解脂质介导的免疫 T2D 中的功能。该提案的长期目标是建立一个新的科学方向了解脂质在促炎症反应、T2D 和自身免疫中的作用的长期目的疾病。该提案通过以下方式测试了脂质抗原呈递是关键机制的总体假设： T2D 中的慢性炎症是由它引发的。这项对脂质抗原的创新研究 T2D 中的演示结合了人类血液样本、转基因和人源化小鼠、单细胞 RNA 的使用测序、多参数细胞因子分析和流式细胞术，以及计算方法允许采用系统生物学方法进行抗原发现和假设测试。在研究领域1，我们将评估 T 细胞反应的脂质抗原依赖性激活。我们将使用人源化小鼠和人类血液样本以探究这些脂质抗原对体外 T 细胞功能的影响（CD1 四聚体负载）和体内（高脂肪饮食）。在研究领域 2，我们将针对脂质抗原呈递来预防和治疗 T2D。这针对第 1 组 CD1 分子和脂质自身抗原的中和抗体抑制的能力人类免疫细胞分泌的促炎细胞因子，用于预防和治疗转基因疾病将评估小鼠。在研究领域 3. T2D 中脂质自身抗原的发现将通过一种新型方法进行用于抗体分析的 3D 打印脂质微阵列。该提案有可能将 T2D 重新定义为由脂质抗原呈递驱动的自身免疫性疾病，并彻底改变治疗策略疾病管理和治疗开发。该提案的结果将允许识别可作为疾病治疗目标的特定炎症途径。