Vascular macrophages and T cells in atherosclerosis
动脉粥样硬化中的血管巨噬细胞和 T 细胞
基本信息
- 批准号:10112954
- 负责人:
- 金额:$ 90.72万
- 依托单位:
- 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:2019-03-18 至 2026-02-28
- 项目状态:未结题
- 来源:
- 关键词:Adoptive TransferAntibodiesAortaApolipoprotein EApolipoproteins BArteriesAtherosclerosisB-LymphocytesBar CodesBlood VesselsCD4 Positive T LymphocytesCardiovascular DiseasesCellsCholesterolClinicalClinical DataColorCytometryDNA MethylationData SetDietDoseEpigenetic ProcessEpitopesExogenous FactorsFOXP3 geneFibrinogenGenderHIVHigh Fat DietHumanImmunotherapyIncubatedInflammationInflammatoryInterleukin-2MeasuresMinorMusMyocardial InfarctionPeptidesPeripheral Blood Mononuclear CellPopulationProteinsProtocols documentationReagentRegulatory T-LymphocyteResearch DesignRoleSolidStrokeT cell receptor repertoire sequencingT-LymphocyteTestingTranslatingVaccinationVaccinesWomanWorkcase controlcell typechronic inflammatory diseaseeffector T cellhistone methylationhuman dataimprovedin vivoinsightmacrophagemouse modelpeptide Bphenotypic datapreventsingle-cell RNA sequencingtranscription factortranscriptomevaccine developmentvaccine efficacyvaccine evaluation
项目摘要
Abstract
This application proposes research designed to provide solid mechanistic underpinnings for immunotherapy
and vaccination to prevent and treat atherosclerosis. Vaccination with MHC-II restricted peptide epitopes from
apolipoprotein B (ApoB) ameliorates atherosclerosis by inducing ApoB-specific regulatory CD4 T cells (Tregs).
I have developed reagents (tetramers and dextramers) to detect and isolate these ApoB-specific Tregs at the
single cell level in mice and humans. The proposed work has a T cell aspect, currently supported by R01
HL121697 (2014-2018), and a vascular macrophage aspect, currently supported by R01 HL115232 (2012-
2022). To gain better mechanistic insight, I propose to adoptively transfer ApoB-specific Tregs (if necessary
expanded in Rag2-/- mice) into recipient mice and measure atherosclerosis. I will also transfer ApoB peptide-
specific antibodies to formally test possible antibody effects, and test the role of B cells in two B cell-deficient
mouse lines. I will study changes in functions of vascular macrophages in vivo after vaccination. To improve
the vaccine efficacy, I propose to test vaccine formulations similar to what would be used clinically, test the
atherosclerosis vaccines in two other mouse models of atherosclerosis (Apoe-/- on chow diet, Ldlr-/- on high fat
diet), optimize the vaccination protocol, and add low-dose IL-2 to stabilize Tregs. To discover how and why
Tregs switch to effector T cells, I will use FoxP3 (the Treg defining transcription factor) lineage tracker mice.
TCR-Seq will test the hypothesis that the apparent switch is caused by an outgrowth of a minor population of
pro-inflammatory ApoB-specifc CD4 T cells. To test cell-exogenous factors, I will incubate ApoB-specific CD4
T cells with explanted normal or atherosclerotic aortas, and measure epigenetic changes by DNA and histone
methylation around the FoxP3 locus. To prepare for translating the vaccine into humans, I propose more
human work, including mass cytometry (CyTOF) on peripheral blood mononuclear cells (PBMCs) with 42-
“color” panels. Barcoded scRNA-Seq to obtain single cell transcriptomes will define the cell types more deeply.
I propose to expand the current clinical data set (all women, most HIV+) to both genders and HIV-. When this
work is completed, we will have a good understanding how atherosclerosis vaccination works. We will have
extensive human data for the phenotype of ApoB-specific CD4 T cells in PBMCs collected from cardiovascular
disease cases and controls.
摘要
这项申请提出了旨在为免疫治疗提供坚实的机制基础的研究
以及预防和治疗动脉粥样硬化的疫苗接种。用来自人的MHC-II限制性肽表位接种
载脂蛋白B(ApoB)通过诱导ApoB特异性调节性CD 4 T细胞(TcB)来改善动脉粥样硬化。
我已经开发了试剂(四聚体和右旋糖酐),以检测和分离这些载脂蛋白B特异性T细胞,
小鼠和人类的单细胞水平。拟议的工作具有T细胞方面,目前由R 01支持
HL 121697(2014-2018)和血管巨噬细胞方面,目前由R 01 HL 115232(2012- 2018)支持
2022年)。为了获得更好的机制见解,我建议采用转移ApoB特异性TdR(如果必要的话
在Rag 2-/-小鼠中扩增)转移到受体小鼠中并测量动脉粥样硬化。我还会把载脂蛋白B肽
特异性抗体正式测试可能的抗体效应,并测试B细胞在两种B细胞缺陷型中的作用。
鼠标线。我将研究疫苗接种后体内血管巨噬细胞功能的变化。提高
疫苗的有效性,我建议测试疫苗配方类似于将用于临床,测试
在另外两种动脉粥样硬化小鼠模型(Apoe-/-,食物饮食,Ldlr-/-,高脂饮食)中的动脉粥样硬化疫苗
饮食),优化疫苗接种方案,并添加低剂量IL-2以稳定TcB。去发现
为了将Treg转换为效应T细胞,我将使用FoxP 3(Treg定义转录因子)谱系追踪小鼠。
TCR-Seq将检验这样的假设,即明显的转换是由少数群体的生长引起的。
促炎性ApoB特异性CD 4 T细胞。为了测试细胞外源性因子,我将孵育载脂蛋白B特异性CD 4
T细胞与正常或动脉粥样硬化斑块,并通过DNA和组蛋白测量表观遗传变化
FoxP 3基因座周围的甲基化。为了准备将疫苗转化为人类,我建议更多
人的工作,包括对外周血单核细胞(PBMC)进行的42-
“颜色”面板。获得单细胞转录组的条形码scRNA-Seq将更深入地定义细胞类型。
我建议将目前的临床数据集(所有妇女,大多数艾滋病毒阳性)扩大到性别和艾滋病毒阴性。当这个
这项工作完成后,我们将很好地了解动脉粥样硬化疫苗的工作原理。我们会一起
从心血管疾病患者采集的PBMC中ApoB特异性CD 4 T细胞表型的广泛人体数据
疾病病例和控制。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Klaus F. Ley其他文献
Binding of function‐blocking mAbs to mouse and human P‐selectin glycoprotein ligand‐1 peptides with and without tyrosine sulfation
功能阻断单克隆抗体与小鼠和人 P-选择素糖蛋白配体 1 肽(有或没有酪氨酸硫酸化)的结合
- DOI:
- 发表时间:
2002 - 期刊:
- 影响因子:5.5
- 作者:
Aravinda Thatte;S. Ficarro;K. Snapp;M. Wild;D. Vestweber;D. Hunt;Klaus F. Ley - 通讯作者:
Klaus F. Ley
Serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) correlate with severity of ileitis in experimental Crohn's disease: A novel marker of small intestinal inflammation
- DOI:
10.1016/s0016-5085(00)85325-1 - 发表时间:
2000-04-01 - 期刊:
- 影响因子:
- 作者:
Jesus Rivera-Nieves;R. Cartland Burns;Christopher A. Moskaluk;Theresa T. Pizarro;Klaus F. Ley;Fabio Cominelli - 通讯作者:
Fabio Cominelli
α<sub>4</sub>β<sub>1</sub>integrin (VLA-4) blockade reduces neointimal growth after carotid air desiccation injury in the ApoE (−/−) mouse
- DOI:
10.1016/s0735-1097(02)80085-7 - 发表时间:
2002-03-06 - 期刊:
- 影响因子:
- 作者:
Kurt G. Barringhaus;J.William Phillips;John M. Sanders;Ann C. Czamik;Klaus F. Ley;Ian J. Sarembock - 通讯作者:
Ian J. Sarembock
Klaus F. Ley的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Klaus F. Ley', 18)}}的其他基金
Mechanism of kindlin-3-dependent integrin activation
kindlin-3依赖性整合素激活机制
- 批准号:
10676897 - 财政年份:2020
- 资助金额:
$ 90.72万 - 项目类别:
Mechanism of kindlin-3-dependent integrin activation
kindlin-3依赖性整合素激活机制
- 批准号:
10229369 - 财政年份:2020
- 资助金额:
$ 90.72万 - 项目类别:
Vascular macrophages and T cells in atherosclerosis
动脉粥样硬化中的血管巨噬细胞和 T 细胞
- 批准号:
10369710 - 财政年份:2019
- 资助金额:
$ 90.72万 - 项目类别:
Vascular macrophages and T cells in atherosclerosis
动脉粥样硬化中的血管巨噬细胞和 T 细胞
- 批准号:
9895858 - 财政年份:2019
- 资助金额:
$ 90.72万 - 项目类别:
Vascular macrophages and T cells in atherosclerosis
动脉粥样硬化中的血管巨噬细胞和 T 细胞
- 批准号:
10623034 - 财政年份:2019
- 资助金额:
$ 90.72万 - 项目类别:
Vascular macrophages and T cells in atherosclerosis
动脉粥样硬化中的血管巨噬细胞和 T 细胞
- 批准号:
10565907 - 财政年份:2019
- 资助金额:
$ 90.72万 - 项目类别:
Core E: Cell sorting, CyTOF and RNA-Seq
核心 E:细胞分选、CyTOF 和 RNA-Seq
- 批准号:
10188604 - 财政年份:2017
- 资助金额:
$ 90.72万 - 项目类别:
Core B: Single Cell Protein and RNA Sequencing Core
核心 B:单细胞蛋白质和 RNA 测序核心
- 批准号:
10334092 - 财政年份:2017
- 资助金额:
$ 90.72万 - 项目类别:
Project 4: APOB-specific CD4 and CD8 T cells exacerbate atherosclerosis
项目4:APOB特异性CD4和CD8 T细胞加剧动脉粥样硬化
- 批准号:
10334097 - 财政年份:2017
- 资助金额:
$ 90.72万 - 项目类别:
相似海外基金
University of Aberdeen and Vertebrate Antibodies Limited KTP 23_24 R1
阿伯丁大学和脊椎动物抗体有限公司 KTP 23_24 R1
- 批准号:
10073243 - 财政年份:2024
- 资助金额:
$ 90.72万 - 项目类别:
Knowledge Transfer Partnership
Role of Natural Antibodies and B1 cells in Fibroproliferative Lung Disease
天然抗体和 B1 细胞在纤维增生性肺病中的作用
- 批准号:
10752129 - 财政年份:2024
- 资助金额:
$ 90.72万 - 项目类别:
CAREER: Next-generation protease inhibitor discovery with chemically diversified antibodies
职业:利用化学多样化的抗体发现下一代蛋白酶抑制剂
- 批准号:
2339201 - 财政年份:2024
- 资助金额:
$ 90.72万 - 项目类别:
Continuing Grant
Isolation and characterisation of monoclonal antibodies for the treatment or prevention of antibiotic resistant Acinetobacter baumannii infections
用于治疗或预防抗生素耐药鲍曼不动杆菌感染的单克隆抗体的分离和表征
- 批准号:
MR/Y008693/1 - 财政年份:2024
- 资助金额:
$ 90.72万 - 项目类别:
Research Grant
Developing first-in-class aggregation-specific antibodies for a severe genetic neurological disease
开发针对严重遗传神经系统疾病的一流聚集特异性抗体
- 批准号:
10076445 - 财政年份:2023
- 资助金额:
$ 90.72万 - 项目类别:
Grant for R&D
Discovery of novel nodal antibodies in the central nervous system demyelinating diseases and elucidation of the mechanisms through an optic nerve demyelination model
发现中枢神经系统脱髓鞘疾病中的新型节点抗体并通过视神经脱髓鞘模型阐明其机制
- 批准号:
23K14783 - 财政年份:2023
- 资助金额:
$ 90.72万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Elucidation of the mechanisms controlling the physicochemical properties and functions of supercharged antibodies and development of their applications
阐明控制超电荷抗体的理化性质和功能的机制及其应用开发
- 批准号:
23KJ0394 - 财政年份:2023
- 资助金额:
$ 90.72万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Role of antibodies in hepatitis E virus infection
抗体在戊型肝炎病毒感染中的作用
- 批准号:
10639161 - 财政年份:2023
- 资助金额:
$ 90.72万 - 项目类别:
Defining the protective or pathologic role of antibodies in Post-Ebola Syndrome
定义抗体在埃博拉后综合症中的保护或病理作用
- 批准号:
10752441 - 财政年份:2023
- 资助金额:
$ 90.72万 - 项目类别:
Human CMV monoclonal antibodies as therapeutics to inhibit virus infection and dissemination
人 CMV 单克隆抗体作为抑制病毒感染和传播的治疗药物
- 批准号:
10867639 - 财政年份:2023
- 资助金额:
$ 90.72万 - 项目类别: