# Role of TRPV4 mechanotransduction in foreign body response

> **NIH NIH R01** · UNIV OF MARYLAND, COLLEGE PARK · 2020 · $419,197

## Abstract

Implantable biomaterials and medical devices are used in millions of procedures each year worldwide.
However, in large number of patients, the implantation of these devices often leads to the development of a
foreign body response (FBR), a chronic inflammatory condition that can ultimately lead to implant failure, which
may cause harm to or death of the patient. The FBR consists of persistent inflammation coupled with fibrous
encapsulation around the implant. There are no effective medical treatments. Hallmarks of the FBR include
activation of macrophages at the tissue-implant interface, formation of destructive foreign body giant cells
(FBGCs), and development of fibrous tissue that encapsulates the implant. The overall goal of our research is
to understand the molecular mechanisms of the fibrotic response. Activated macrophages are thought to
orchestrate the FBR by secreting inflammatory mediators. Emerging data support a critical role for a
mechanical signal, e.g., substrate stiffness, in macrophage activation. However, a critical gap in this field is that
the identity of the plasma membrane mechanosensor by which the mechanical signal is transduced/maintained
is not known, nor are the downstream consequences of mechano-receptor signaling on the FBR. These gaps
pose a significant barrier to progress in the field. In recent, exciting preliminary data, we obtained evidence that
TRPV4, an ion channel in the transient receptor potential vanilloid family, and which is a known
mechanosensor, may be the mediator of FBR. Specifically, we found that: 1) Trpv4 deletion in mice prevented
macrophage accumulation, FBGC formation, and collagen accumulation in a subcutaneous implantation
model; 2) the severity of the in vivo macrophage accumulation at the tissue-implant interface was dependent
on the stiffness of the implant, and 3) genetic ablation or pharmacologic antagonism of TRPV4 blocked
macrophage adhesion and spreading on stiff matrix, interleukin-4-induced FBGC formation, and inflammatory
gene expression in both human and mouse bone marrow derived macrophages. Our preliminary data indicated
that TRPV4 activity (Ca2+ influx) was augmented in response to increased matrix stiffness, and suggested that
the molecular pathway linking TRPV4 activity to the FBR involved a specific phosphoinositide 3-kinase (PI3K)
isoform, PI3K-alpha. The objective of this proposal is to determine the role of TRPV4 in the FBR. Based on our
preliminary data, our central hypothesis is that TRPV4 mediates the FBR to biomaterials by increasing
macrophage activation and fibrogenesis in a manner dependent on substrate stiffness and PI3K-alpha. We will
utilize innovative technologies, in vivo and in vitro model systems, and a recently identified small molecule
TRPV4 inhibitor to test the hypothesis with two Specific Aims. In Specific Aim 1 we will test the hypothesis that
TRPV4 is a necessary component of the FBR in vivo; and in Specific Aim 2 we will test the hypothesis that
mecha...

## Key facts

- **NIH application ID:** 9966986
- **Project number:** 5R01EB024556-04
- **Recipient organization:** UNIV OF MARYLAND, COLLEGE PARK
- **Principal Investigator:** Shaik O Rahaman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $419,197
- **Award type:** 5
- **Project period:** 2017-09-10 → 2022-06-07

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9966986

## Citation

> US National Institutes of Health, RePORTER application 9966986, Role of TRPV4 mechanotransduction in foreign body response (5R01EB024556-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9966986. Licensed CC0.

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