Project 3: Leukocyte-Mediated Regulation of Cardiorenal Syndrome

项目3:白细胞介导的心肾综合征调节

基本信息

  • 批准号:
    10397000
  • 负责人:
  • 金额:
    $ 43.59万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-05-01 至 2025-04-30
  • 项目状态:
    未结题

项目摘要

Summary HF affects 6.5 million Americans, with almost 1 million new cases per year and costing over $30 billion in healthcare resources. Renal dysfunction (RD) is common in HF, with a reported prevalence over 50%, and is a major risk factor for death. Ultimately, cardiac dysfunction promotes renal fibrotic remodeling and progressive HF-induced RD, a pathophysiologic condition known as cardiorenal syndrome (CRS). Importantly, RD in HF is a potent marker of decreased survival, outperforming traditional metrics of HF disease severity like ejection fraction and functional class, however fundamental research into the mechanisms behind this process are limited. A number of factors preceding fibrosis contribute to the development of CRS, including changes in hemodynamics, neurohormones, cytokines and sympathetic nervous system (SNS) activation. Responsive to each of these changes are leukocytes, including neutrophils, monocytes, macrophages and lymphocytes, some of which have been implicated in CRS. However, few reports have investigated whether they play a reactionary or causative role in the development of CRS-induced renal dysfunction and remodeling in response to HF or how to mitigate their impact in this process. We hypothesize that leukocytes play a fundamental role in regulating CRS, and since RD remains a strong independent predictor for poor prognosis in HF patients, understanding the role of leukocytes and the molecular changes they undergo during CRS progression may offer new strategies by which to alleviate patient mortality. Therefore, we will determine the temporal- and subtype-specific leukocyte infiltration profiles in relation to changes in cardiac and renal structure and function during CRS progression, the impact of their deletion at specific timepoints, as well as perform a dynamic single cell transcriptome analysis of renal cells during CRS and transcriptome analyses of peripheral blood leukocytes from mice and humans with clinically-manifested CRS. In addition, our lab recently showed that modulation of leukocyte-specific β2-adrenergic receptor (β2AR) expression or signaling alters leukocyte targeting and responsiveness to injury in a GPCR kinase (GRK)/β-arrestin (βarr)-dependent manner. Thus, we will define the impact of leukocyte-specific β2AR-dependent signaling on CRS progression and determine how genetic deletion, pharmacologic inhibition or GRK/βarr-biased modulation of leukocyte β2AR signaling impacts CRS development and progression. Completion of this project will generate new molecular and physiologic insight toward the detection and treatment of HF-induced CRS via targeting of leukocyte-dependent processes and responsiveness.
概括 心力衰竭影响 650 万美国人,每年新增近 100 万例心力衰竭病例,造成的损失超过 300 亿美元 医疗保健资源。肾功能不全 (RD) 在 HF 中很常见,据报道患病率超过 50%,并且 死亡的主要危险因素。最终,心功能障碍促进肾纤维化重塑和 进行性心力衰竭引起的 RD,一种称为心肾综合征 (CRS) 的病理生理状况。重要的是, 心力衰竭中的 RD 是生存率下降的有效标志,优于心力衰竭疾病严重程度的传统指标,例如 射血分数和功能类别,但是对该过程背后的机制进行基础研究 是有限的。纤维化之前的许多因素都会导致慢性鼻窦炎的发生,包括 血流动力学、神经激素、细胞因子和交感神经系统 (SNS) 激活。响应 这些变化中的每一个都是白细胞,包括中性粒细胞、单核细胞、巨噬细胞和淋巴细胞, 其中一些与 CRS 有关。然而,很少有报告调查他们是否发挥作用 在 CRS 诱导的肾功能障碍和响应重塑的发展中起反作用或因果作用 HF 或如何减轻其在此过程中的影响。我们假设白细胞在 调节 CRS,并且由于 RD 仍然是心力衰竭患者预后不良的强有力的独立预测因子, 了解白细胞的作用及其在 CRS 进展过程中经历的分子变化可能 提供降低患者死亡率的新策略。因此,我们将确定时间和 与心脏和肾脏结构和功能变化相关的亚型特异性白细胞浸润特征 在 CRS 进展期间,在特定时间点删除它们的影响,以及执行动态单一 CRS 期间肾细胞的细胞转录组分析和外周血转录组分析 来自患有临床表现的 CRS 的小鼠和人类的白细胞。此外,我们的实验室最近表明 调节白细胞特异性 β2 肾上腺素能受体 (β2AR) 表达或信号传导会改变白细胞 以 GPCR 激酶 (GRK)/β-抑制蛋白 (βarr) 依赖性方式对损伤的靶向和响应。因此,我们 将定义白细胞特异性 β2AR 依赖性信号传导对 CRS 进展的影响,并确定如何 基因缺失、药物抑制或白细胞 β2AR 信号转导影响的 GRK/βarr 偏向调节 CRS 的发展和进展。该项目的完成将产生新的分子和生理学 通过针对白细胞依赖性过程来检测和治疗 HF 诱导的 CRS 的见解 和反应能力。

项目成果

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Douglas Tilley其他文献

Douglas Tilley的其他文献

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{{ truncateString('Douglas Tilley', 18)}}的其他基金

Project 3: Leukocyte-Mediated Regulation of Cardiorenal Syndrome
项目3:白细胞介导的心肾综合征调节
  • 批准号:
    10612837
  • 财政年份:
    2020
  • 资助金额:
    $ 43.59万
  • 项目类别:
Beta adrenergic receptor-dependent regulation of leukocytes in acute cardiac injury
急性心脏损伤中白细胞的β肾上腺素受体依赖性调节
  • 批准号:
    10288087
  • 财政年份:
    2017
  • 资助金额:
    $ 43.59万
  • 项目类别:
Beta adrenergic receptor-dependent regulation of leukocytes in acute cardiac injury
急性心脏损伤中白细胞的β肾上腺素受体依赖性调节
  • 批准号:
    10063903
  • 财政年份:
    2017
  • 资助金额:
    $ 43.59万
  • 项目类别:
Molecular Mechanisms of Cardiac beta1AR-EGFR Association and Signaling
心脏 β1AR-EGFR 关联和信号转导的分子机制
  • 批准号:
    8204906
  • 财政年份:
    2010
  • 资助金额:
    $ 43.59万
  • 项目类别:
Molecular Mechanisms of Cardiac beta1AR-EGFR Association and Signaling
心脏 β1AR-EGFR 关联和信号转导的分子机制
  • 批准号:
    8794455
  • 财政年份:
    2010
  • 资助金额:
    $ 43.59万
  • 项目类别:
b1AR-mediated EGFR transactivation in the heart
b1AR 介导的心脏 EGFR 反式激活
  • 批准号:
    9242051
  • 财政年份:
    2010
  • 资助金额:
    $ 43.59万
  • 项目类别:
Molecular Mechanisms of Cardiac beta1AR-EGFR Association and Signaling
心脏 β1AR-EGFR 关联和信号转导的分子机制
  • 批准号:
    8601944
  • 财政年份:
    2010
  • 资助金额:
    $ 43.59万
  • 项目类别:
Molecular Mechanisms of Cardiac beta1AR-EGFR Association and Signaling
心脏 β1AR-EGFR 关联和信号转导的分子机制
  • 批准号:
    8434133
  • 财政年份:
    2010
  • 资助金额:
    $ 43.59万
  • 项目类别:
Molecular Mechanisms of Cardiac beta1AR-EGFR Association and Signaling
心脏 β1AR-EGFR 关联和信号转导的分子机制
  • 批准号:
    8020288
  • 财政年份:
    2010
  • 资助金额:
    $ 43.59万
  • 项目类别:
b1AR-mediated EGFR transactivation in the heart
b1AR 介导的心脏 EGFR 反式激活
  • 批准号:
    9106627
  • 财政年份:
    2010
  • 资助金额:
    $ 43.59万
  • 项目类别:

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