# Extracellular matrix sensing in cellular signaling, migration and wound repair

> **NIH NIH R01** · HENRY M. JACKSON FDN FOR THE ADV MIL/MED · 2020 · $310,791

## Abstract

PROJECT SUMMARY/ABSTRACT
Human genetic mutations in integrins and other adhesion proteins cause a range of autoimmune diseases and
likely contribute to the chronic inflammation that accompanies many widespread human maladies. However, our
knowledge of the molecular mechanisms that link integrin function and immune activation remain incomplete.
The long-term goal of this research program is to address this knowledge gap by revealing novel regulatory
connections between extracellular matrix (ECM) sensing and macrophage activation. The overall objective of
this proposal is to evaluate how ECM sensing (which we refer to as ‘haptosensing’) tunes macrophage activation
at the molecular and cellular levels, and to translate this understanding to in vivo wound healing studies. The
central hypothesis of this proposal is that haptosensing regulates macrophage activation via integrin-Arp2/3
dependent crosstalk with immune receptors. Strong preliminary data generated by the applicant’s lab supports
this hypothesis, as well as demonstrating that the proposed studies are feasible in the applicant’s hands. The
rationale for the proposed research plan is that gaining mechanistic insight into haptosensing will allow us to
begin understanding its role in chronic human disease states, which may in turn reveal potential pharmacological
targets. The hypothesis will be tested further in the context of three specific aims: 1) Define the integrin-initiated
signals that activate Arp2/3 during haptosensing; 2) Determine how the haptosensing pathway tunes
inflammatory macrophage activation; 3) Determine how macrophage haptosensing is required for wound
resolution in vivo. These aims will primarily be pursued by mechanistically dissecting macrophage behavior in
custom-designed microfluidic chambers and translating these in vitro findings to in vivo settings using intravital
multiphoton microscopy. These studies will employ loss of function approaches (genetic nulls, shRNA
knockdown, inhibitor wash-in), which are already established and are effective in the applicant’s hands. Finally,
the applicant’s lab will employ careful, rigorous image analysis approaches to study cell migration, actin
dynamics and subcellular protein localization in primary macrophages, in vitro and in vivo, responding to
numerous extracellular cues, including ECM gradients. The approach is innovative, as it applies mechanistic
observations generated in vitro to direct observations of immune cell migration and activity in vivo. The
approaches employed to this end by the applicant’s lab represent significant technological advances that make
it possible to clarify the connection between cellular adhesion and macrophage activation. The proposed
research program is significant as completion of these aims will identify the mechanistic details of macrophage
haptosensing and will assign an in vivo function to it. The significant conceptual and technological advances
brought to bear in this research study will h...

## Key facts

- **NIH application ID:** 10006014
- **Project number:** 5R01GM134104-02
- **Recipient organization:** HENRY M. JACKSON FDN FOR THE ADV MIL/MED
- **Principal Investigator:** Jeremy Rotty
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $310,791
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10006014

## Citation

> US National Institutes of Health, RePORTER application 10006014, Extracellular matrix sensing in cellular signaling, migration and wound repair (5R01GM134104-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10006014. Licensed CC0.

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