Role of Islet-Infiltrating Lymphocytes in Obesity

胰岛浸润淋巴细胞在肥胖中的作用

基本信息

  • 批准号:
    9094462
  • 负责人:
  • 金额:
    $ 23.78万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-06-24 至 2018-05-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Obesity has reached epidemic proportions, affecting more than one third of Americans with almost 10 percent of Americans affected by type 2 diabetes (T2D). T2D is considered a metabolic disease that is largely induced by obesity, while type 1 diabetes (T1D) is an immune-mediated disease. However, multiple hallmarks of T1D can be detected in some T2D patients, suggesting that an islet-specific autoimmune component could be present in obesity and/or T2D. This application will investigate the role of islet-infiltrating lymphocytes in obesity with the goal of understanding how breaks in lymphocyte tolerance lead to altered beta function. We discovered that T cells and B cells infiltrate the isles in the high fat fed, diet induced obesity model which develops insulin resistance resulting in pre-T2D. These islet-infiltrating lymphocytes had a high percentage of regulatory T cells. However, virtually nothing is known about the function of lymphocytes within the islets during obesity. The human disease relevance of our finding is supported by a study that found lymphocyte infiltration in the islets of T2D patients. Also present in obesity is systemic inflammation that i characterized by circulating inflammatory cytokines and local islet and adipose inflammation that is promoted by the accumulation of classically activated (M1) mononuclear phagocytes. M1 mononuclear phagocytes promote beta cell dysfunction and death, while alternatively activated (M2) mononuclear phagocytes are associated with normal islets and islet repair. In obesity, there is also evidence to suggest that there are lymphocytes that are autoreactive for adipose tissue antigens. If obesity-induced inflammation can induce a break in immunological tolerance to adipose antigens can it also induce a break in tolerance to islet antigens? We hypothesize that in obesity, islet-infiltrating effector lymphocytes are islet-specific and promote beta cell dysfunction and death, in part through activation of M1 mononuclear phagocytes; however, local regulatory lymphocytes control M1 mononuclear phagocyte- mediated inflammation to maintain beta cell function. To test this hypothesis we propose the following aims: (1) to determine if in obesity, islet-infiltrating T cells and B cells are islet-antigen specific; (2) to determine the efect of islet-infiltrating lymphocyte subsets on beta cell death and dysfunction; and (3) to determine how islet- infiltrating lymphocyte subsets affect the number, phenotype and function of mononuclear phagocytes in the islets. Understanding the function of islet-infiltrating lymphocytes in obesity could change our understanding of how obesity alters lymphocyte tolerance leading to susceptibility to both T1D and T2D, thereby revealing new areas of therapeutic intervention to support beta cell function and survival in both forms of diabetes.
 描述(由申请人提供):肥胖已达到流行病的比例,影响超过三分之一的美国人,近10%的美国人患有2型糖尿病(T2 D)。T2 D被认为是一种代谢性疾病,主要由肥胖引起,而1型糖尿病(T1 D)是一种免疫介导的疾病。然而,在一些T2 D患者中可以检测到T1 D的多种标志,这表明肥胖和/或T2 D中可能存在胰岛特异性自身免疫组分。本申请将研究胰岛浸润淋巴细胞在肥胖中的作用,目的是了解淋巴细胞耐受性的破坏如何导致β功能改变。我们发现T细胞和B细胞浸润高脂肪喂养的饮食诱导的肥胖模型中的岛,其发展胰岛素抗性,导致前T2 D。这些胰岛浸润淋巴细胞具有高比例的调节性T细胞。然而,几乎没有人知道肥胖期间胰岛内淋巴细胞的功能。我们发现的人类疾病相关性得到了一项研究的支持,该研究发现T2 D患者胰岛中存在淋巴细胞浸润。肥胖症中还存在以循环炎性细胞因子为特征的全身性炎症以及由经典活化(M1)单核吞噬细胞的积累促进的局部胰岛和脂肪炎症。M1单核吞噬细胞促进β细胞功能障碍和死亡,而交替激活(M2)单核吞噬细胞与正常胰岛和胰岛修复相关。在肥胖症中,也有证据表明存在对脂肪组织抗原具有自身反应性的淋巴细胞。如果肥胖引起的炎症可以诱导对脂肪抗原的免疫耐受性的破坏,那么它也可以诱导对胰岛抗原的耐受性的破坏吗?我们假设,在肥胖症中,胰岛浸润效应淋巴细胞是胰岛特异性的,部分通过激活M1单核吞噬细胞促进β细胞功能障碍和死亡;然而,局部调节淋巴细胞控制M1单核吞噬细胞介导的炎症,以维持β细胞功能。为了检验这一假设,我们提出以下目标:(1)确定在肥胖症中,胰岛浸润性T细胞和B细胞是否是胰岛抗原特异性的;(2)确定胰岛浸润性淋巴细胞亚群对β细胞死亡和功能障碍的影响;和(3)确定胰岛浸润性淋巴细胞亚群如何影响胰岛中单核吞噬细胞的数量、表型和功能。了解胰岛浸润淋巴细胞在肥胖中的功能可以改变我们对肥胖如何改变淋巴细胞耐受性导致对T1 D和T2 D易感性的理解,从而揭示治疗干预的新领域,以支持β细胞功能和两种形式的糖尿病的生存。

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 }}

Rachel S Friedman其他文献

Rachel S Friedman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('Rachel S Friedman', 18)}}的其他基金

Single Cell Genomics to Resolve Control of Immune Cell Function During Type 1 Diabetes
单细胞基因组学解决 1 型糖尿病期间免疫细胞功能的控制问题
  • 批准号:
    10728072
  • 财政年份:
    2023
  • 资助金额:
    $ 23.78万
  • 项目类别:
MerTK Mediated T Cell Suppression in the Pancreatic Islets During Type 1 Diabetes
1 型糖尿病期间 MerTK 介导的胰岛 T 细胞抑制
  • 批准号:
    10054623
  • 财政年份:
    2020
  • 资助金额:
    $ 23.78万
  • 项目类别:
MerTK Mediated T Cell Suppression in the Pancreatic Islets During Type 1 Diabetes
1 型糖尿病期间 MerTK 介导的胰岛 T 细胞抑制
  • 批准号:
    9218916
  • 财政年份:
    2017
  • 资助金额:
    $ 23.78万
  • 项目类别:
Mertk Mediated T Cell Suppression in the Pancreatic Islets During Type 1 Diabetes
1 型糖尿病期间 Mertk 介导的胰岛 T 细胞抑制
  • 批准号:
    10736476
  • 财政年份:
    2017
  • 资助金额:
    $ 23.78万
  • 项目类别:
Role of Islet-Infiltrating Lymphocytes in Obesity
胰岛浸润淋巴细胞在肥胖中的作用
  • 批准号:
    8953834
  • 财政年份:
    2015
  • 资助金额:
    $ 23.78万
  • 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:
    $ 23.78万
  • 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:
    $ 23.78万
  • 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:
    $ 23.78万
  • 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:
    $ 23.78万
  • 项目类别:
    Fellowship
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:
    $ 23.78万
  • 项目类别:
    Research Grant
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:
    $ 23.78万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
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:
    $ 23.78万
  • 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:
    $ 23.78万
  • 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:
    $ 23.78万
  • 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:
    $ 23.78万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了