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Imaging CMKLR1 to Track Macrophage-Driven Inflammation in Post-Myocardial Infarction Remodeling

Award Number: R01HL186219
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/10/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Imaging CMKLR1 to Track Macrophage-Driven Inflammation in Post-Myocardial Infarction Remodeling - ABSTRACT Post-myocardial infarction (MI) heart failure is a leading cause of morbidity and mortality, driven in part by chronic macrophage-mediated inflammation that promotes maladaptive extracellular matrix (ECM) remodeling and fibrosis through interactions of macrophages and fibroblasts. Despite strong preclinical evidence supporting the pathogenic role of macrophage-fibroblast crosstalk, immunomodulatory therapies targeting this interaction have not yet successfully translated to clinical practice. A key barrier is the lack of noninvasive tools to identify patients with sustained myocardial inflammation who may benefit from such therapies and to monitor treatment response. Positron emission tomography (PET) of inflammatory pathways offers a promising strategy to fill this gap. However, currently available tracers either lack specificity for macrophages or are limited to detecting early monocyte infiltration, failing to capture chronic inflammation driven by long-lived macrophages. Here, we propose a novel imaging approach targeting chemokine-like receptor 1 (CMKLR1), a receptor highly expressed by recruited macrophages and implicated in profibrotic macrophage-fibroblast crosstalk through its interaction with its fibroblast-derived ligand RARRES2. Our central goal is to validate CMKLR1-targeted PET as a tool for noninvasive monitoring of ongoing myocardial inflammation, predicting the risk of post-MI heart failure, and assessing response to immunomodulatory therapies in a murine MI model. We will also determine the clinical relevance of our approach by analyzing publicly available transcriptomic datasets from patients with ischemic cardiomyopathy to determine whether myocardial expression of CMKLR1 and RARRES2 identifies individuals with a transcriptomic profile indicative of active inflammation and ECM remodeling. Our central hypothesis is that CMKLR1-targeted PET allows for risk stratification and therapeutic monitoring during post-MI cardiac remodeling by detecting the burden of recruited profibrotic macrophages. We propose three Specific Aims (SA): SA-1: To evaluate CMKLR1 as a biomarker of A) macrophage-fibroblast crosstalk in a murine MI model; and B) active inflammation and ECM remodeling in patients with ischemic cardiomyopathy. SA-2: To validate the accuracy of CMKLR1-targeted PET in tracking macrophage accumulation during the progression of post-MI myocardial remodeling in a murine model. SA-3: To investigate A) the potential of CMKLR1-targeted PET to prognosticate and monitor the response to immunomodulatory therapies in MI; and B) the efficacy of CMKLR1 blockade to ameliorate post-MI heart failure. Impact: This project will establish a novel imaging strategy for risk stratification and monitoring treatment response in post-MI heart failure, ultimately promoting a precision approach to the targeted use of immunomodulatory therapies in patients with persistent inflammation and ECM remodeling. Considering the central role of macrophages in other cardiac diseases, such as myocarditis and sarcoidosis, this approach may have broad translational relevance across a wide range of cardiac inflammatory diseases.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $1,559,091 )
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cardiovascular Diseases Research	000	1	7/16/2026	NEW	$1,559,091
														Subtotal = $1,559,091

Grand Total All Awards = $1,559,091

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Imaging CMKLR1 to Track Macrophage-Driven Inflammation in Post-Myocardial Infarction Remodeling

Award Number: R01HL186219

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/10/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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