课题基金 / 基金详情

Beta adrenergic receptor-dependent regulation of leukocytes in acute cardiac injury

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
负责人:
Douglas Tilley
金额:
$39.63万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-12-15 至 2022-11-30

项目摘要

项目成果

Douglas Tilley的其他基金

相似基金

相关文献

中文摘要
翻译
摘要
英文摘要
Abstract As a neurodegenerative disease affecting a growing number of people in the U.S. and worldwide each year, Alzheimer's disease (AD) is marked by a series of pathophysiological features in the cortex and hippocampus, ultimately leading to cognitive dysfunction and dementia. Importantly, while the frequency of AD increases as the population ages, there is a lack of effective treatment options for mitigating the development or progression of this disease, which will lead to an enormous financial and healthcare burden on society in the coming decades as well as decreased quality of life for those patients and their primary caregivers. Understanding the contributing factors to the development of this disease is imperative to enable the development of an array of therapeutics to alleviate this growing crisis in the ageing population. Neuroinflammation is recognized to be associated with the development of AD and AD-related pathophysiology, and immune cells to play roles in this process. Peripheral leukocytes have been suggested to contribute to this neuroinflammatory response and impact the development of AD-related pathophysiology, although the extent to which they play a role in this process remains uncertain. Thus, we aim to characterize peripheral leukocyte accumulation in the cortical- hippocampal regions in a model of AD toward the development of novel therapeutics to modulate their responsiveness to AD-related pathophysiology. Our recent work has demonstrated that deletion of leukocyte- expressed β2AR leads to alterations in immune cell localization and responsiveness to injury. Notably, these effects were mediated via G protein-coupled receptor kinase (GRK)/β-arrestin (βarr)-dependent signaling, as expression of a GRK/βarr-coupled, but not a G protein-coupled, β2AR was capable of restoring normal leukocyte parameters. Translationally, we demonstrated that β-blockers with selectivity toward β2AR exert the same molecular effects on leukocytes and response to injury in mice and in human leukocytes and lymphoid tissues. In relation to these observations, studies have reported beneficial effects of β-blockers on AD-related neuropathology in humans and animal models of AD, however the specific impact of peripheral leukocyte- expressed β2AR on these effects is not known. Thus, we aim to determine whether leukocyte-expressed β2AR impacts the progression of AD-related pathophysiology via regulation of leukocyte accumulation in the cortical and hippocampal regions of the brain. Overall, we hypothesize that inflammatory peripheral leukocytes are differentially recruited into the cortex/hippocampus at different timepoints during disease progression and that leukocyte-specific deletion of β2AR will reduce the development and progression of AD-related neuropathology. Further, we hypothesize that GRK/βarr-biased β2AR signaling in particular will be responsible for these effects, representing a novel therapeutic direction in which to dampen the progression of AD-related pathophysiology.
期刊论文(10)
专著(0)
科研奖励(0)
会议论文
DOI: 10.1093/cvr/cvab044
发表时间: 2022-01-07
期刊: Cardiovascular research
影响因子: 10.8
作者: [de Lucia C, Grisanti LA, Borghetti G, Piedepalumbo M, Ibetti J, Lucchese AM, Barr EW, Roy R, Okyere AD, Murphy HC, Gao E, Rengo G, Houser SR, Tilley DG, Koch WJ]
通讯作者: Koch WJ
The Role of Leukocytes in Diabetic Cardiomyopathy.
白细胞在糖尿病心肌病中的作用。
DOI: 10.3389/fphys.2018.01547
发表时间: 2018
期刊: Frontiers in physiology
影响因子: 4
作者: [Bajpai A, Tilley DG]
通讯作者: Tilley DG
DOI: 10.1016/j.cophys.2020.09.007
发表时间: 2021-03
期刊: Current opinion in physiology
影响因子: 2.5
作者: [Nayak TK, Tilley DG]
通讯作者: Tilley DG
DOI: 10.7150/thno.26619
发表时间: 2018
期刊: Theranostics
影响因子: 12.4
作者: [Grisanti LA, Thomas TP, Carter RL, de Lucia C, Gao E, Koch WJ, Benovic JL, Tilley DG]
通讯作者: Tilley DG
Project 3: Leukocyte-Mediated Regulation of Cardiorenal Syndrome
  • 批准号:
    10612837
  • 项目类别:
  • 资助金额:
    $43.59万
  • 财政年份:
    2020
  • 负责人:
    Douglas Tilley
  • 依托单位:
Project 3: Leukocyte-Mediated Regulation of Cardiorenal Syndrome
  • 批准号:
    10397000
  • 项目类别:
  • 资助金额:
    $43.59万
  • 财政年份:
    2020
  • 负责人:
    Douglas Tilley
  • 依托单位:
Beta adrenergic receptor-dependent regulation of leukocytes in acute cardiac injury
  • 批准号:
    10063903
  • 项目类别:
  • 资助金额:
    $39.63万
  • 财政年份:
    2017
  • 负责人:
    Douglas Tilley
  • 依托单位:
Molecular Mechanisms of Cardiac beta1AR-EGFR Association and Signaling
  • 批准号:
    8204906
  • 项目类别:
  • 资助金额:
    $38.25万
  • 财政年份:
    2010
  • 负责人:
    Douglas Tilley
  • 依托单位:
海外基金