# Functional Involvement of IntegrinB4/ITGB4 and Kindlin/FERMT2 in Focal Adhesion Dynamic Remodeling in ARDS

> **NIH NIH P01** · UNIVERSITY OF FLORIDA · 2023 · $405,176

## Abstract

ABSTRACT:
The elevated ARDS mortality observed in the COVID-19 pandemic has highlighted the contribution of excessive
mechanical stress produced by mechanical ventilation in promoting lethal increases in lung vascular permea-
bility. Integrin β4 (ITGB4 gene) and kindlin-2 (FERMT2 gene) are essential adhesion molecules in endothelial
cell (EC) focal adhesions (FAs), structures critical for mechano-sensing, for bidirectional signaling between
the EC cytoskeleton and the cell-matrix interface, and for EC barrier regulation. The mechanistic basis for dy-
namic FA coordination during inflammatory EC barrier dysfunction and subsequent barrier restoration is a fun-
damental question that remains unresolved. We speculate that coordinate control of FA structures requires
the dynamic interactions of integrin β4 (ITGB4) and kindlin-2 with key PPG cytoskeletal effectors (nmMLCK,
cortactin, Dock1, lamellipodin, paxillin) to efficiently assemble functional FAs during EC barrier responses (pe-
ripheral cytoskeletal remodeling, lamellipodial formation, gap closure). ITGB4 is a unique mechano-sensing,
laminin-binding integrin, and kindlin-2 is a multi-domain mechano-sensing adapter FA protein that recruits struc-
tural and signaling molecules to FAs in concert with cytoskeletal rearrangement. We speculate that these EC
responses are highly influenced by ITGB4 and kindlin-2 post-translational modifications (PTMs) and coding pol-
ymorphisms (SNPs). As reactive oxygen species (ROS) is an important stimulus for FA dynamics and loss of
EC barrier integrity, with Core B, SA #1 will characterize the role of three ROS-sensing transcription factors
(NRF2, HIF1α/HIF2α), ITGB4/FERMT2 SNPs and DNA methylation in genetic/epigenetic regulation of
ITGB4/FERMT2 expression and the influence on generation of the unique ITGB4 alternatively-spliced, barrier-
regulatory variant, Integrin β4E (ITGB4E), that we identified as involved in mechano-sensing and EC barrier
regulation. With Core D, SA #2 will conduct in depth structure/function studies including 3D live cell imaging of
mutant ITGB4 and kindlin-2 fusion proteins (SNPs, PTMs) to characterize ITGB4/kindlin-2 function in spatially-
specific EC cytoskeletal rearrangements driving EC barrier-disruption and barrier-restoration. SA #3 will examine
the functionality of ITGB4/kindlin-2 interactions within lamellipodia with known and novel FA-binding cytoskeletal
partners, including cortactin, Dock1, lamellipodin and highly novel interactions with nmMLCK (Project #1).
Finally, utilizing elegant rat and porcine models of LPS/VILI (Core C), SA #4 will assess the therapeutic utility of
the SMURF inhibitor A01, or SRI-38832 to augment kindlin-2 expression as cargo in TySIPonate-conjugated
liposomes (TySIPosomes, Project #4). Project #3 studies will determine the structure/function and molecular
basis for the dynamic FA control by ITGB4 and kindlin-2 and yield important insights into functional relevance of
this unique FA signaling axis in r...

## Key facts

- **NIH application ID:** 10871783
- **Project number:** 7P01HL126609-07
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** ANNE E CRESS
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $405,176
- **Award type:** 7
- **Project period:** 2016-09-20 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10871783

## Citation

> US National Institutes of Health, RePORTER application 10871783, Functional Involvement of IntegrinB4/ITGB4 and Kindlin/FERMT2 in Focal Adhesion Dynamic Remodeling in ARDS (7P01HL126609-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10871783. Licensed CC0.

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