# Efferocytosis-Directed Inflammation Resolution and Repair in the Hypoxic Heart

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $564,908

## Abstract

Thorp Project Summary Abstract-Resubmission.
Heart failure after acute myocardial infarction (AMI) is a significant cause of morbidity and
mortality. Though pharmacological advances have significantly reduced mortality, the residual
risk of post AMI-induced heart failure is increasing. This compels the development of new
approaches to preserve the integrigty of cardiac tissue after injury. The extent of tissue damage
in the acute phase of AMI is a critical determinant of the degree of subsequent adverse
remodeling that leads to impaired cardiac performance. As such, an important goal is to
minimize infarct size and its expansion, which are a function of cardiomyocyte death and
ineffecient tissue repair. Efficient phagocytic removal of dying cardiomyocytes by efferocytosis is
critical to initiating resolving inflammation and to heart healing. For example, reduced
efferocytosis of dying cardiomyocytes is directly correlated with increased morbidity and
mortality post AMI. Recent studies have also shown macrophage subsets to be differentially
responsible for phagocytic and repair functions in the heart. Beyond the cellular level, the
molecular pathways within myocardial phagocytes that regulate efferocytosis-directed
inflammation resolution in the heart, remain unknown. The Thorp laboratory has made the
recent discovery that maladaptive inactivation of efferocytosis signaling pathways worsen heart
repair after AMI, paving the way for a new class of molecular targets to enhance heart healing.
Our studies newly reveal that the apoptotic cell receptors of the TAM family, MerTK and AXL,
surprisingly act though distinct mechanisms to regulate cardiomyocyte efferocytosis and
myocardial inflammation resolution. Our data in non-gene targeted mice and humans also
suggest that AXL is naturally inhibited during AMI by proteolysis. These initial findings led to
important new lines of investigation. This includes: (I) The degree to which AXL uniquely
functions in macrophages to regulate AMI repair in the hypoxic heart, including how this may be
exploited for thereapeutic intervention. (II) Novel TAM receptor-dependent and -independent
immunometabolic mechanisms of efferocytosis and inflammation resolution and (III) the
unknown causal role of AXL proteolysis post AMI in mice and patients. Thus, these new Aims
are poised to make significant advances in the still relatively understudied process of
efferocytosis in heart, efferocytic immunometabolic signaling, and the basic biology of TAM
receptors. Newly created tools, including novel gene-engineered experimental animals, will
assist in rigorous testing of the aforementioned principles and are of significance to both cardiac
inflammation and broader principles of tissue injury.

## Key facts

- **NIH application ID:** 9888089
- **Project number:** 2R01HL122309-06A1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Edward Benjamin Thorp
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $564,908
- **Award type:** 2
- **Project period:** 2014-04-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9888089

## Citation

> US National Institutes of Health, RePORTER application 9888089, Efferocytosis-Directed Inflammation Resolution and Repair in the Hypoxic Heart (2R01HL122309-06A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9888089. Licensed CC0.

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