# Role of Cilp1 in Post-Natal Heart Response to Injury

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $560,734

## Abstract

Matricellular proteins are constituents of the extracellular matrix (ECM). They are normally expressed highly
during embryonic development but absent/low in adult tissues unless activated by cues for tissue remodeling.
Matricellular proteins shape ECM properties through interactions with structural proteins, growth factors, and cell
receptors during organ development and differentiation. In an attempt to identify molecular signatures unique to
irreversible cardiac fibrosis, we performed proteomics of fibrotic heart and liver and found that cartilage
intermediate layer protein 1 (Cilp1) is differentially upregulated in the infarcted heart. Cilp1 is normally associated
with bone and cartilage development. Its function and mechanism of action in adult heart diseases are unknown.
We generated Cilp1 knockout (KO) mice from commercial Cilp1fl/fl mice and transgenic (Tg) mice with Cilp1
overexpressed in myofibroblasts. While deletion of Cilp1 reduced adverse cardiac remodeling upon myocardial
infarction (MI), overexpression of Cilp1 worsened it. Cilp1 is expressed predominantly in cardiac fibroblasts. We
hypothesize that fibroblast Cilp1 promotes inflammation and myofibroblast proliferation upon MI injury. We now
generated fibroblast conditional fbKO mice (PostnMCM;Cilp1fl/fl and Tcf21MCM;Cilp1fl/fl that contain a tamoxifen
inducible Cre-recombinase expression cassette within Periostin (Postn) and Tcf21 genetic locus, respectively).
Aim 1. To determine the cell-type specific function of Cilp1 in post-MI cardiac remodeling. We will delete Cilp1
in cardiac fibroblasts before and post-MI day (d) 1 & d4 to investigate its effect on cardiac remodeling, including
cardiac function, inflammation, myofibroblast proliferation/differentiation, and collagen remodeling. We will also
perform proteomics of myofibroblasts isolated from these mouse hearts. The role of fibroblast Cilp1 in regulation
of gene transcription in various heart cell types will be investigated with single-nuclei RNA-seq of infarcted WT
and Cilp1 fbKO hearts at post-MI d3. Aim 2. To establish the molecular function of Cilp1 and its mechanism of
action. Preliminary studies showed that Cilp1 protein in culture medium promotes myofibroblast proliferation via
the mTORC1 pathway and binds scavenge receptor CD36. Cilp1 may interact with cell receptor/growth factor,
promoting cell proliferation and inflammatory gene expression via receptor-mediated signaling pathways. To test
this hypothesis, we will identify the minimal functional domain(s) of Cilp1 via mutagenesis and potential Cilp1-
binding partners using both screen- and candidate-based assays and will establish how Cilp1 may act as a
paracrine factor to regulate the cellular phenotypes of various heart cell types via receptor-mediated signaling
pathways. We will also measure blood level of Cilp1 in mice before and after an anti-fibrogenic therapy upon MI
injury. Matricellular proteins are clinically tractable owing to their accessibility to system...

## Key facts

- **NIH application ID:** 10365053
- **Project number:** 1R01HL157050-01A1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Zhi-Ping Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $560,734
- **Award type:** 1
- **Project period:** 2022-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10365053

## Citation

> US National Institutes of Health, RePORTER application 10365053, Role of Cilp1 in Post-Natal Heart Response to Injury (1R01HL157050-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10365053. Licensed CC0.

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