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

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2021 · $396,250

## Abstract

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 progress...

## Key facts

- **NIH application ID:** 10288087
- **Project number:** 3R01HL139522-04S1
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Douglas Tilley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $396,250
- **Award type:** 3
- **Project period:** 2017-12-15 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10288087

## Citation

> US National Institutes of Health, RePORTER application 10288087, Beta adrenergic receptor-dependent regulation of leukocytes in acute cardiac injury (3R01HL139522-04S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10288087. Licensed CC0.

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