Mechanisms of Immune Activation in Hypertension
高血压的免疫激活机制
基本信息
- 批准号:10543181
- 负责人:
- 金额:$ 75.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-02-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAffectAntigen-Presenting CellsBiological MarkersCD8-Positive T-LymphocytesCellsCollaborationsDataDendritic CellsDiseaseExperimental ModelsHealthcareHistocompatibility Antigens Class IHumanHypertensionIL17 geneImmunizationIndividualInflammationInterferon Type IIKidney DiseasesLipidsMajor Histocompatibility ComplexMass Spectrum AnalysisMitochondriaMusMyocardial InfarctionNADPH OxidaseNatural ImmunityPathogenicityPeptidesProcessProliferatingProteinsPublic HealthReactive Oxygen SpeciesResearchSeverity of illnessSourceStrokeT memory cellT-Cell ActivationT-Cell ReceptorT-LymphocyteT-Lymphocyte SubsetsUnited Statesadaptive immunityadductcare burdenhypertensiveimmune activationimmunogenicmonocyteneoantigensnoveloxidationpreventprogramssingle cell sequencingtranslational immunology
项目摘要
PROJECT SUMMARY
In recent years, it has become apparent that both innate and adaptive immunity contribute to the genesis of
hypertension. We have discovered a novel mechanism that underlies activation of adaptive immunity in
hypertension, involving the formation of isolevuglandins (isoLGs) in dendritic cells (DCs) and other antigen
presenting cells. These lipid oxidation products adduct to proteins, resulting in formation of neoantigens that
are processed and presented by major histocompatibility complexes (MHCs). IsoLG-modified proteins are
increased in DCs of both mice and humans with hypertension and drive proliferation of subsets of T cells,
particularly CD8+ T cells. In this research program, we are examining mechanisms responsible for formation of
isoLGs in DCs. We have evidence that isoLGs are formed as a result of both NADPH oxidase activation and
by reactive oxygen species generated by the mitochondria in DCs. Using unique mice we have made we are
defining potential immunogenic peptides presented in MHC class 1 and determining if there are different
peptides derived from mitochondria versus non-mitochondrial sources. Mass spectroscopy will also be
employed to determine if similar isoLG modified peptides are presented by monocytes of humans with
hypertension. In parallel studies performed in collaboration with Dr. Simon Mallal, the director of the
Translational Immunology Core at Vanderbilt, we are characterizing the alpha and beta chain sequences of T
cell receptors (TCRα and TCRβ) in activated T cells of both mice and humans using single cell sequencing.
This will allow us to produce surrogate T cells (transfectomas) that can be used to determine their
responsiveness to isoLG-modified proteins and peptides presented in MHC class 1 of hypertensive mice. We
have recently shown that hypertensive humans have a striking increase in circulating memory T cells that
produce IL-17A and IFN-γ compared to matched controls. Data from single cell sequencing will identify the
TCRα and TCRβ of these cells and to produce transfectomas expressing these sequences and to determine if
they are also responsive to isoLG modified proteins presented in the context of APCs from the same individual.
Identifying specific neoantigens in hypertension will provide an enormous advance in understanding this
disease. These could serve as biomarkers of disease severity and be used to detect pathogenic T cells in
hypertension. Ultimately immunization approaches could be employed to treat or prevent hypertension.
Specific therapies to reduce isoLG formation have proven effective in experimental models and have
substantial promise for treatment of human hypertension.
项目总结
近年来,先天免疫和获得性免疫都明显地促进了肺炎的发生。
高血压。我们发现了一种新的机制,它是激活适应性免疫的基础
高血压,包括在树突状细胞(DC)和其他抗原中形成异uglandins(IsUGs)
呈现细胞。这些脂质氧化产物加成到蛋白质上,导致形成新的抗原,
由主要组织相容性复合体(MHC)处理和呈递。IsoLG修饰的蛋白质是
高血压小鼠和人类的DC增加,并推动T细胞亚群的增殖,
尤其是CD8+T细胞。在这个研究项目中,我们正在研究负责形成
DC中的IsoLGs。我们有证据表明,isLGs的形成是NADPH氧化酶活化和
由DC中的线粒体产生的活性氧物种。使用我们制造的独一无二的老鼠
定义在MHC 1类中存在的潜在免疫原肽并确定是否存在不同的
线粒体来源的多肽与非线粒体来源的多肽。质谱学也将被
用来确定人类单核细胞是否呈递类似的等位基因修饰的多肽
高血压。与西蒙·马拉尔博士合作进行的平行研究,该中心主任
翻译免疫学核心在Vanderbilt,我们正在描述T的α和β链序列
用单细胞测序法测定小鼠和人活化T细胞中的细胞受体(TcRα和TcRβ)。
这将使我们能够产生替代T细胞(转染瘤),可以用来确定他们的
高血压小鼠对等Lg修饰的蛋白质和多肽的反应性。我们
最近研究表明,高血压患者的循环记忆T细胞显著增加
与对照组比较产生IL-17A和干扰素-γ。来自单细胞测序的数据将识别出
TcRα和TcRβ,并产生表达这些序列的转染瘤,并确定
它们也对来自同一个体的APC背景中出现的等LG修饰蛋白作出反应。
识别高血压的特定新抗原将为理解这一点提供巨大的进步。
疾病。这些可以作为疾病严重程度的生物标志物,并用于检测患者的致病T细胞
高血压。最终,可以采用免疫方法来治疗或预防高血压。
减少等低密度脂蛋白形成的特定疗法在实验模型中已被证明有效,并已
为人类高血压的治疗带来了巨大的希望。
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 }}
David G Harrison其他文献
Effects of Interleukin-1β Inhibition on Blood Pressure, Incident Hypertension, and Residual Inflammatory Risk
IL-1β 抑制对血压、高血压和残余炎症风险的影响
- DOI:
- 发表时间:
2019 - 期刊:
- 影响因子:8.3
- 作者:
A. Rothman;Jean G Macfadyen;T. Thuren;A. Webb;David G Harrison;T. Guzik;P. Libby;R. Glynn;P. Ridker - 通讯作者:
P. Ridker
Posttranscriptional Regulation of Endothelial Nitric Oxide Synthase during Cell Growth Materials and Methods Cell Culture
细胞生长过程中内皮一氧化氮合酶的转录后调节 材料和方法 细胞培养
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
Charles D. Searles;Yoichi Miwa;David G Harrison;S. Ramasamy;D. Searles - 通讯作者:
D. Searles
Isolevuglandins promote autoimmunity and hypertension in systemic lupus erythematosus
异黄兰素促进系统性红斑狼疮的自身免疫和高血压
- DOI:
10.1101/2020.02.10.20021741 - 发表时间:
2020 - 期刊:
- 影响因子:0
- 作者:
David M. Patrick;N. Visitación;M. Ormseth;C. M. Stein;Sean S. Davies;Valery N. Yermalitsky;V. Amarnath;Leslie J. Crofford;Jonathan M Williams;S. Dikalov;A. Dikalova;Liang Xiao;Justin P. Van Beusecum;Mingfang Ao;A. Fogo;Kirabo Annet;David G Harrison - 通讯作者:
David G Harrison
88 - The Redox Sensitive Inactivation of Mitochondrial Sirt3, SOD2 Hyperacetylation and Complex I Superoxide Production in Endothelial Dysfunction and Hypertension
- DOI:
10.1016/j.freeradbiomed.2015.10.128 - 发表时间:
2015-10-01 - 期刊:
- 影响因子:
- 作者:
Anna E Dikalova;Hanna A Itani;Rafal R Nazarewicz;William G McMaster;Joshua P Fessel;Jorge L Gamboa;David G Harrison;Sergey Dikalov - 通讯作者:
Sergey Dikalov
A dynamical neural simulation mapping feature-based attention to location with non-linear cortical circuits
- DOI:
10.1186/1471-2202-12-s1-p55 - 发表时间:
2011-07-18 - 期刊:
- 影响因子:2.300
- 作者:
David G Harrison;Marc de Kamps - 通讯作者:
Marc de Kamps
David G Harrison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('David G Harrison', 18)}}的其他基金
Common Inflammation Pathways between Aging and Hypertension That Weaken Bone
衰老和高血压之间削弱骨骼的常见炎症途径
- 批准号:
10430633 - 财政年份:2022
- 资助金额:
$ 75.15万 - 项目类别:
Common Inflammation Pathways between Aging and Hypertension That Weaken Bone
衰老和高血压之间削弱骨骼的常见炎症途径
- 批准号:
10618349 - 财政年份:2022
- 资助金额:
$ 75.15万 - 项目类别:
Vanderbilt Hypertension and Blood Pressure Regulation Program
范德比尔特高血压和血压调节计划
- 批准号:
10385839 - 财政年份:2019
- 资助金额:
$ 75.15万 - 项目类别:
Vanderbilt Hypertension and Blood Pressure Regulation Program
范德比尔特高血压和血压调节计划
- 批准号:
10597621 - 财政年份:2019
- 资助金额:
$ 75.15万 - 项目类别:
Mechanisms of T cell Activation in Hypertension
高血压中 T 细胞激活的机制
- 批准号:
9978625 - 财政年份:2016
- 资助金额:
$ 75.15万 - 项目类别:
The Role of Inflammation in Cardiovascular Disease
炎症在心血管疾病中的作用
- 批准号:
9978598 - 财政年份:2016
- 资助金额:
$ 75.15万 - 项目类别:
The Role of The T Cell In The Genesis of Hypertension
T 细胞在高血压发生中的作用
- 批准号:
9273740 - 财政年份:2015
- 资助金额:
$ 75.15万 - 项目类别:
相似海外基金
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 75.15万 - 项目类别:
Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 75.15万 - 项目类别:
Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 75.15万 - 项目类别:
Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 75.15万 - 项目类别:
Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 75.15万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 75.15万 - 项目类别:
Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 75.15万 - 项目类别:
Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
- 批准号:
2301846 - 财政年份:2023
- 资助金额:
$ 75.15万 - 项目类别:
Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 75.15万 - 项目类别:
Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
- 批准号:
23K16076 - 财政年份:2023
- 资助金额:
$ 75.15万 - 项目类别:
Grant-in-Aid for Early-Career Scientists