Mechanistic Role of CD4+ T-Cells in Atherosclerotic Renal Artery Stenosis

CD4 T 细胞在动脉粥样硬化性肾动脉狭窄中的机制作用

基本信息

  • 批准号:
    8849763
  • 负责人:
  • 金额:
    $ 4.43万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-04-01 至 2017-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Atherosclerotic renal artery stenosis (ARAS) is a condition where narrowing of the renal artery decreases blood flow to the kidney and leads to development of renal atrophy and hypertension. ARAS is a major cause of renal failure. It is present in over 7% of individuals over 65 years, in up to 45% of patients with coronary artery disease, and in up to 17% of patients with both type II diabetes and hypertension. Optimal management of patients with ARAS is controversial as both revascularization and/or pharmaceutical treatment often fails to improve renal function. Current paradigms point to inflammatory M1 macrophages as the immune mediator in the development of renal injury in ARAS. However, recent studies suggest that CD4+ T cell activation and differentiation into inflammatory Th1 T cells might be the initial events that lead to M1 macrophage recruitment and differentiation in the stenotic kidney. Despite this correlation between T cells and ARAS, the mechanisms by which T cells are recruited, activated, and mediate development of inflammation, renal injury, and atrophy in the stenotic kidney are not well defined. This is the focus of the proposed studies. We hypothesize that the antigen-independent activation and recruitment of Th1 T cells into the stenotic kidney by renal dendritic cells mediates injury by promoting M1 macrophage differentiation. To test this hypothesis, we develop three specific aims. First, we will determine if renal dendritic cells are necessary for CD4+ T cell recruitment after renal artery stenosis in a mouse model. Our hypothesis predicts that renal dendritic cells are necessary for CD4+ T cell recruitment to the stenotic kidney. To test this idea, we will induce renal artery stenosis in a mouse model lacking dendritic cells and determine if lack of dendritic cells reduces CD4+ T cell activation and thereby protects the stenotic kidney from atrophy. Second, we will address whether antigen-mediated T cell activation is necessary for CD4+ T cell participation in kidney damage after renal artery stenosis in a mouse model. We will induce renal artery stenosis in a transgenic mouse containing only T cells that are specific for a non-self- antigen, and determine if lack of self-antigen protects the stenotic kidney from atrophy. Third, we will determine if Th1 T cells mediate the development of renal injury by promoting M1 macrophage differentiation after renal artery stenosis in mice models. To test this idea, we will induce renal artery stenosis in mice with T cells that are unable to differentiate into Th1 cells and in mice with macrophages that are unable to differentiate into M1 macrophages. The proposed studies will identify immune responses that could be targeted for effective treatment. Thus, the results of these studies will lead to a better understanding of the mechanistic role of CD4+ T cells in the pathophysiology of ARAS, and could potentially lead to development of novel therapy for treatment of this disease.
描述(由申请人提供):动脉粥样硬化性肾动脉狭窄(ARAS)是一种肾动脉狭窄减少流向肾脏的血流并导致肾萎缩和高血压发展的疾病。ARAS是肾衰竭的主要原因。它存在于超过7%的65岁以上的个体中,高达45%的冠状动脉疾病患者中,高达17%的II型糖尿病和高血压患者中。ARAS患者的最佳管理存在争议,因为血运重建和/或药物治疗通常无法改善肾功能。目前的范例指出,炎性M1巨噬细胞作为免疫介质在ARAS肾损伤的发展。然而,最近的研究表明,CD 4 + T细胞活化和分化为炎性Th 1 T细胞可能是导致狭窄肾脏中M1巨噬细胞募集和分化的初始事件。尽管T细胞和ARAS之间存在这种相关性,但T细胞被募集、激活和介导狭窄肾脏中炎症、肾损伤和萎缩发展的机制尚未明确。这是拟议研究的重点。我们推测,抗原非依赖性活化和招募Th 1 T细胞进入狭窄的肾脏,肾树突状细胞介导的损伤,促进M1巨噬细胞分化。为了验证这一假设,我们制定了三个具体目标。首先,我们将在小鼠模型中确定肾树突状细胞是否是肾动脉狭窄后CD 4 + T细胞募集所必需的。我们的假设预测,肾树突状细胞是必要的CD 4 + T细胞募集到狭窄的肾脏。为了验证这一想法,我们将在缺乏树突状细胞的小鼠模型中诱导肾动脉狭窄,并确定缺乏树突状细胞是否会降低CD 4 + T细胞活化,从而保护狭窄的肾脏免受萎缩。其次,我们将讨论抗原介导的T细胞活化是否是必要的CD 4 + T细胞参与肾动脉狭窄后的小鼠模型中的肾损伤。我们将在仅含有对非自身抗原特异性的T细胞的转基因小鼠中诱导肾动脉狭窄,并确定缺乏自身抗原是否保护狭窄的肾脏免于萎缩。 第三,我们将确定Th 1 T细胞是否通过促进小鼠肾动脉狭窄后M1巨噬细胞分化来介导肾损伤的发展。为了验证这一想法,我们将在T细胞不能分化为Th 1细胞的小鼠和巨噬细胞不能分化为M1巨噬细胞的小鼠中诱导肾动脉狭窄。拟议中的研究将确定可用于有效治疗的免疫反应。因此,这些研究的结果将导致更好地理解CD 4 + T细胞在ARAS病理生理学中的机制作用,并可能导致开发治疗这种疾病的新疗法。

项目成果

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Stella P Hartono其他文献

Stella P Hartono的其他文献

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{{ truncateString('Stella P Hartono', 18)}}的其他基金

Mechanistic Role of CD4+ T-Cells in Atherosclerotic Renal Artery Stenosis
CD4 T 细胞在动脉粥样硬化性肾动脉狭窄中的机制作用
  • 批准号:
    8712668
  • 财政年份:
    2014
  • 资助金额:
    $ 4.43万
  • 项目类别:

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