# Project 3: Leukocyte-Mediated Regulation of Cardiorenal Syndrome

> **NIH NIH P01** · TEMPLE UNIV OF THE COMMONWEALTH · 2021 · $435,875

## Abstract

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.

## Key facts

- **NIH application ID:** 10145772
- **Project number:** 5P01HL147841-02
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Douglas Tilley
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $435,875
- **Award type:** 5
- **Project period:** 2020-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10145772

## Citation

> US National Institutes of Health, RePORTER application 10145772, Project 3: Leukocyte-Mediated Regulation of Cardiorenal Syndrome (5P01HL147841-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10145772. Licensed CC0.

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