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: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-15 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10288087
• 关键词: 3xTg-AD mouse; Acute; Administrative Supplement; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease model; Animal Model; Behavior; Brain; Brain region; Cells; Coupled; Dementia; Development; Disease; Disease Progression; Flow Cytometry; Frequencies; Functional disorder; Funding; G protein coupled receptor kinase; GTP-Binding Proteins; Goals; Healthcare; Heart Injuries; Hematopoietic; Hippocampus (Brain); Human; Immune; Immunohistochemistry; Impaired cognition; Inflammatory; Injury; Leukocytes; Lymphoid; Lymphoid Tissue; Mediating; Molecular; Mus; Neurodegenerative Disorders; Observational Study; Patients; Pattern; Peripheral; Phosphotransferases; Play; Population; Process; Proteins; Quality of life; Regulation; Reporting; Role; Series; Signal Pathway; Signal Transduction; Societies; Therapeutic; Time; Work; aging population; beta-adrenergic receptor; beta-arrestin; cognitive function; effective therapy; human model; neuroinflammation; neuropathology; novel therapeutic intervention; novel therapeutics; parent project; prevent; primary caregiver; receptor; recruit; response; response to injury; single-cell RNA sequencing

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.

摘要 作为一种神经退行性疾病，每年在美国和世界范围内影响越来越多的人， 阿尔茨海默病（AD）以皮层和海马中的一系列病理生理学特征为标志， 最终导致认知功能障碍和痴呆。重要的是，虽然AD的频率随着年龄的增长而增加， 随着人口老龄化，缺乏有效的治疗选择来减轻发展或进展， 这种疾病将在未来给社会带来巨大的经济和医疗负担 数十年，以及这些患者及其主要照顾者的生活质量下降。了解 为了开发一系列治疗方法，必须找出这种疾病发展的促成因素 治疗，以缓解这一日益严重的危机，在老龄化人口。神经炎症被认为是 与AD的发生和AD相关的病理生理学有关，而免疫细胞在其中发挥作用 过程外周白细胞被认为有助于这种神经炎症反应， 影响AD相关病理生理学的发展，尽管它们在其中发挥作用的程度 进程仍然不确定。因此，我们的目标是表征外周白细胞在皮质- 海马区在AD模型中的作用，以开发新的治疗方法来调节其 对AD相关病理生理学的反应性。我们最近的研究表明，白细胞的缺失- 表达的β2AR导致免疫细胞定位和对损伤的反应性的改变。值得注意的是，这些 作用是通过G蛋白偶联受体激酶（GRK）/β-抑制蛋白（β-arrestin）依赖性信号传导介导的， GRK/β arr偶联的β 2AR表达，而G蛋白偶联的β2AR表达，能够恢复正常 白细胞参数在翻译方面，我们证明了对β2AR具有选择性的β受体阻滞剂可以发挥作用， 小鼠和人白细胞和淋巴细胞对白细胞和损伤反应的分子效应相同 组织中关于这些观察结果，研究报告了β受体阻滞剂对AD相关的有益作用。 在人类和AD动物模型中的神经病理学，然而，外周白细胞的特定影响， 表达的β 2 AR对这些效应的影响尚不清楚。因此，我们的目标是确定白细胞表达的 β 2 AR通过调节白细胞聚集影响AD相关病理生理学的进展 大脑皮层和海马区。总的来说，我们假设炎性外周血白细胞 在疾病进展期间的不同时间点差异性地募集到皮质/海马中， 白细胞特异性β 2 AR缺失将减少AD相关性脑血管病的发生和进展， 神经病理学此外，我们假设GRK/β arr偏向的β2AR信号尤其是 对于这些效果，代表了一种新的治疗方向，以抑制AD相关的进展， 病理生理学

项目成果

G protein-coupled receptor kinase 5 (GRK5) contributes to impaired cardiac function and immune cell recruitment in post-ischemic heart failure.

• 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

Recent Advances in GPCR-Regulated Leukocyte Responses during Acute Cardiac Injury.

• 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

Pepducin-mediated cardioprotection via β-arrestin-biased β2-adrenergic receptor-specific signaling.

• 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