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:10509043
- 负责人:
- 金额:$ 47.1万
- 依托单位:
- 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:
- 关键词:3D PrintAdipose tissueAmericanAnti-Inflammatory AgentsAntibodiesAntigen PresentationAntigen-Presenting CellsAntigensAreaAutoantibodiesAutoantigensAutoimmune DiseasesAutoimmune ResponsesAutoimmunityAutomobile DrivingB-LymphocytesB-cell receptor repertoire sequencingBiochemistryBiological AssayBiological ModelsBlood specimenCD1 AntigensCell physiologyCellsChronicCommunitiesComplementComputer ModelsComputing MethodologiesCoupledCustomDevelopmentDiseaseDisease ManagementEnzyme-Linked Immunosorbent AssayFatty AcidsFatty acid glycerol estersFlow CytometryGoalsHealthHigh Fat DietHomeostasisHumanImmuneImmune responseImmune systemImmunologicsImmunophenotypingIn VitroInflammationInflammatoryInflammatory ResponseInsulin ResistanceInvestigationLaboratoriesLeftLipidsMediatingMolecular Biology TechniquesMusNatureNon-Insulin-Dependent Diabetes MellitusNonesterified Fatty AcidsOutcomePathway interactionsPatientsPersonsPhenotypePostdoctoral FellowProtein AnalysisProtein EngineeringProteinsResearchRoleSamplingSaturated Fatty AcidsSerumSystems BiologyT cell responseT-Cell ActivationT-Cell ReceptorT-LymphocyteTestingTherapeuticTransgenic MiceTranslationsTriglyceridesWorkcytokinehuman modelhumanized mouseimmune functionin vitro Modelin vivoinnovationmouse modelneutralizing antibodynew technologynew therapeutic targetnovelpreventresponsesingle-cell RNA sequencingtherapeutic development
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.
项目摘要
大量的研究工作已经发现了慢性炎症在胰岛素产生中的关键作用
2型糖尿病(T2D)的症状有哪些?即使有了这个发现,也没有成功的抗炎药
治疗方法已经被开发出来,研究已经停滞,重点是表征脂肪组织
T2D小鼠模型中的炎症。重要的是,T2D中慢性炎症的起始物仍然是
未知2型糖尿病表现为针对多种自身蛋白质的自身抗体,但蛋白质
抗体反应性的筛选尚未发现T2D炎症的引发剂。值得注意的是,
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,
被忽视,可能是由于呈递脂质抗原的蛋白质,即第1组CD1分子,未被表达
对小鼠这种表达的缺乏在我们对免疫学中脂质抗原的理解中留下了一个巨大的漏洞。
体内平衡和疾病,尤其是T2D。为了解决这个问题,我们将使用转基因小鼠,
人类CD1分子和人类免疫应答的体外模型,以了解脂质介导的免疫
T2D功能这项建议的长期目标是建立一个新的科学方向,
了解脂质在促炎反应、T2D和自身免疫中的作用的长期目的
疾病该提案测试了总体假设,即脂质抗原呈递是一个关键机制,
T2D中的慢性炎症开始。这项创新和新颖的研究脂质抗原
T2D中的呈递结合使用人血液样品、转基因和人源化小鼠、单细胞RNA
测序,多参数细胞因子分析和流式细胞术,加上计算方法,
允许系统生物学方法来发现抗原和检验假设。在研究领域1,我们将
评估T细胞应答的脂质抗原依赖性活化。我们将使用人源化的老鼠和人血
样品以询问这些脂质抗原对体外T细胞功能的影响(CD1四聚体加载),
体内(高脂肪饮食)。在研究领域2中,我们将靶向脂质抗原呈递以预防和治疗T2D。的
靶向第1组CD1分子和脂质自身抗原的中和抗体抑制
从人免疫细胞分泌的促炎细胞因子以及预防和治疗转基因动物中的疾病
将对小鼠进行评估。在研究领域3。T2D中的脂质自身抗原发现将使用一种新的
用于抗体分析的3D打印脂质微阵列。该提案有可能将T2D重新定义为一种
脂质抗原呈递驱动的自身免疫性疾病,并完全改变
疾病管理和治疗开发。该提案的结果将允许
识别可用于疾病治疗的特定炎症途径。
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 }}
Dequina Angelina Nicholas其他文献
Dequina Angelina Nicholas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('Dequina Angelina Nicholas', 18)}}的其他基金
Sex Differences in lipid antigen presentation, impact of lipid antigen presentation on peripheral lipid metabolism
脂质抗原呈递的性别差异,脂质抗原呈递对外周脂质代谢的影响
- 批准号:
10818273 - 财政年份:2022
- 资助金额:
$ 47.1万 - 项目类别:
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
- 批准号:
10687176 - 财政年份:2022
- 资助金额:
$ 47.1万 - 项目类别:
The Role of Energy Balance in Gonadotrope and Reproductive Function
能量平衡在促性腺激素和生殖功能中的作用
- 批准号:
10462861 - 财政年份:2021
- 资助金额:
$ 47.1万 - 项目类别:
The Role of Energy Balance in Gonadotrope and Reproductive Function
能量平衡在促性腺激素和生殖功能中的作用
- 批准号:
10731507 - 财政年份:2021
- 资助金额:
$ 47.1万 - 项目类别:
The Role of Energy Balance in Gonadotrope and Reproductive Function
能量平衡在促性腺激素和生殖功能中的作用
- 批准号:
10651835 - 财政年份:2021
- 资助金额:
$ 47.1万 - 项目类别:
The Role of Energy Balance in Gonadotrope and Reproductive Function
能量平衡在促性腺激素和生殖功能中的作用
- 批准号:
10622020 - 财政年份:2021
- 资助金额:
$ 47.1万 - 项目类别:
The Role of Energy Balance in Gonadotrope and Reproductive Function
能量平衡在促性腺激素和生殖功能中的作用
- 批准号:
10477443 - 财政年份:2021
- 资助金额:
$ 47.1万 - 项目类别:
The Role of Energy Balance in Gonadotrope and Reproductive Function
能量平衡在促性腺激素和生殖功能中的作用
- 批准号:
10022156 - 财政年份:2019
- 资助金额:
$ 47.1万 - 项目类别:
The Role of Energy Balance in Gonadotrope and Reproductive Function
能量平衡在促性腺激素和生殖功能中的作用
- 批准号:
9892573 - 财政年份:2019
- 资助金额:
$ 47.1万 - 项目类别:
Palmitic Acid Regulation of Dendritic Cell Toll-Like Receptor 4 Signaling
棕榈酸对树突状细胞 Toll 样受体 4 信号传导的调节
- 批准号:
8598252 - 财政年份:2013
- 资助金额:
$ 47.1万 - 项目类别:
相似海外基金
Deciphering the role of adipose tissue in common metabolic disease via adipose tissue proteomics
通过脂肪组织蛋白质组学解读脂肪组织在常见代谢疾病中的作用
- 批准号:
MR/Y013891/1 - 财政年份:2024
- 资助金额:
$ 47.1万 - 项目类别:
Research Grant
ESTABLISHING THE ROLE OF ADIPOSE TISSUE INFLAMMATION IN THE REGULATION OF MUSCLE MASS IN OLDER PEOPLE
确定脂肪组织炎症在老年人肌肉质量调节中的作用
- 批准号:
BB/Y006542/1 - 财政年份:2024
- 资助金额:
$ 47.1万 - 项目类别:
Research Grant
Activation of human brown adipose tissue using food ingredients that enhance the bioavailability of nitric oxide
使用增强一氧化氮生物利用度的食品成分激活人体棕色脂肪组织
- 批准号:
23H03323 - 财政年份:2023
- 资助金额:
$ 47.1万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Development of new lung regeneration therapies by elucidating the lung regeneration mechanism of adipose tissue-derived stem cells
通过阐明脂肪组织干细胞的肺再生机制开发新的肺再生疗法
- 批准号:
23K08293 - 财政年份:2023
- 资助金额:
$ 47.1万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Canadian Alliance of Healthy Hearts and Minds: Dissecting the Pathways Linking Ectopic Adipose Tissue to Cognitive Dysfunction
加拿大健康心灵联盟:剖析异位脂肪组织与认知功能障碍之间的联系途径
- 批准号:
479570 - 财政年份:2023
- 资助金额:
$ 47.1万 - 项目类别:
Operating Grants
Determinants of Longitudinal Progression of Adipose Tissue Inflammation in Individuals at High-Risk for Type 2 Diabetes: Novel Insights from Metabolomic Profiling
2 型糖尿病高危个体脂肪组织炎症纵向进展的决定因素:代谢组学分析的新见解
- 批准号:
488898 - 财政年份:2023
- 资助金额:
$ 47.1万 - 项目类别:
Operating Grants
A study on the role of brown adipose tissue in the development and maintenance of skeletal muscles
棕色脂肪组织在骨骼肌发育和维持中作用的研究
- 批准号:
23K19922 - 财政年份:2023
- 资助金额:
$ 47.1万 - 项目类别:
Grant-in-Aid for Research Activity Start-up
A mechanism of lipid accumulation in brown adipose tissue
棕色脂肪组织中脂质积累的机制
- 批准号:
10605981 - 财政年份:2023
- 资助金额:
$ 47.1万 - 项目类别:
Obesity and Childhood Asthma: The Role of Adipose Tissue
肥胖和儿童哮喘:脂肪组织的作用
- 批准号:
10813753 - 财政年份:2023
- 资助金额:
$ 47.1万 - 项目类别:
Estrogen Signaling in the Ventromedial Hypothalamus Modulates Adipose Tissue Metabolic Adaptation
下丘脑腹内侧区的雌激素信号调节脂肪组织代谢适应
- 批准号:
10604611 - 财政年份:2023
- 资助金额:
$ 47.1万 - 项目类别: