# Investigating the role of the complement system in cardiac regeneration

> **NIH NIH F32** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $67,446

## Abstract

Project summary:
The mammalian heart has a limited regenerative potential due to the low proliferation rate of adult
cardiomyocytes. However, a narrow regenerative window has been identified in the neonatal murine heart,
wherein mice are able to successfully regenerate their hearts both at the tissue and functional level
following injury. In a cross-species transcriptomic screen in the Lee laboratory, inflammatory response
genes including complement receptors were upregulated in a conserved manner in the regenerating heart
of three model organisms – axolotl, mouse and zebrafish. The most-upregulated inflammatory response
genes include G-protein coupled receptors (GPCR) for complement components, complement 5a receptor
(C5aR1) and complement 3a receptor (C3aR). The complement system is part of the innate immune
system and functions to clear foreign material. Activation of an early immune response is a shared feature
observed in the regenerating heart of model organisms, consistent with the upregulation of C5aR1 and
C3aR observed. C5aR1 is a GPCR that functions as a complement receptor for C5a, generated by
proteolytic cleavage of complement component 5. Pharmacologic inhibition of C5aR1 after apical resection
results in an impaired cardiomyocyte proliferative response in all three model organisms studied – axolotl,
mouse and zebrafish. I propose to investigate the role of complement activation in murine cardiac
regeneration, to elucidate the molecular mechanisms that initiate effective repair and cardiomyocyte
proliferation in the mammalian heart following injury. To understand the role of C5aR1, I will utilize global
genetic deletion mouse model of C5aR1 to assess cardiac regeneration after apical resection at the cellular,
tissue and functional level in C5aR1 wild-type and C5aR1 knock-out mice. I propose to assess
cardiomyocyte proliferation in C5aR1 wild-type and knock-out mice to understand the sequence of
molecular events in the injured heart that initiate cardiomyocyte proliferation and effective regeneration.
Furthermore, I will investigate the role of C3aR in early cardiac regeneration using pharmacologic inhibition
and C3aR knock-out mice. In addition, I will perform experiments in non-regenerative murine models (7-
day-old mice) to investigate if acute activation of complement signaling (C3 and C5) will increase
cardiomyocyte proliferation following injury. These studies will likely define a mechanistic pathway of early
events critical for the initiation of cardiomyocyte proliferation in the myocardium.

## Key facts

- **NIH application ID:** 10093224
- **Project number:** 7F32HL146000-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Niranjana Natarajan
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $67,446
- **Award type:** 7
- **Project period:** 2019-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10093224

## Citation

> US National Institutes of Health, RePORTER application 10093224, Investigating the role of the complement system in cardiac regeneration (7F32HL146000-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10093224. Licensed CC0.

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