# CARMIL1 and Endothelial Barrier Function Regulation

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2024 · $495,159

## Abstract

ABSTRACT
 The acute respiratory distress syndrome (ARDS) is characterized by pulmonary vascular leak and
flooding of the normally air-filled alveolar space with protein rich edema fluid and causes severe hypoxemia,
respiratory failure and death among critically ill patients. Identification of genetic factors which modify the risk of
developing ARDS or influence clinical outcomes may improve our pathologic understanding of this disease.
Human variants in the gene LRRC16A are implicated in improved ARDS outcomes but the mechanism
remains unknown. LRRC16A encodes capping protein, Arp 2/3 and myosin-I linker (CARMIL1), a cytoskeletal
regulatory protein which has been studied primarily in cell motility. CARMIL contributes to peripheral actin
polymerization by antagonizing capping protein at the end of growing actin strands. Decreased CARMIL
expression slows cell migration by attenuating protrusion of the cell membrane. Maintenance of pulmonary
endothelial cell (EC) barrier function is critical to prevent lung vascular leak. Cytoskeletal rearrangement and
force generation determine barrier integrity through dynamic changes to the plasma membrane and cell shape.
Peripheral actin polymerization protrudes the endothelial cell membrane to increase contact with neighboring
cells, reduce intercellular gaps and increase barrier function. We hypothesize that CARMIL1 is a key regulator
of peripheral actin structure and branched actin polymerization which facilitate membrane protrusion to
determine EC barrier function. This proposal will use complementary biochemical, imaging and functional
studies to characterize the role of CARMIL1 in EC barrier function. We will investigate CARMIL1 in the context
of known regulators of endothelial cytoskeletal and membrane dynamics to improve our understanding of the
mechanisms responsible for pulmonary vascular leak. Specific Aim 1 will investigate the role of CARMIL1 in
EC peripheral actin structures and dynamics by employing biochemical and advanced imaging techniques after
CARMIL1 silencing and/or overexpression of wild-type or variant constructs. Specific Aim 2 will determine the
effect of modified CARMIL1 expression on EC barrier integrity using multiple assays of local and global
permeability. Specific Aim 3 will characterize the function of endothelial CARMIL1 in murine lung injury.
Endothelial specific delivery of siRNA and lentiviral constructs will investigate the effect of CARMIL1 manipulation
on the intact lung vasculature following inflammatory or infectious insults. These studies will provide novel
mechanistic insights into the cellular mechanisms of ARDS and provide a link between CARMIL1 variants and
clinical outcomes. This knowledge has the potential to identify new therapeutic targets and improve the care of
future patients.

## Key facts

- **NIH application ID:** 10981549
- **Project number:** 1R01HL170118-01A1
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Patrick Belvitch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $495,159
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10981549

## Citation

> US National Institutes of Health, RePORTER application 10981549, CARMIL1 and Endothelial Barrier Function Regulation (1R01HL170118-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10981549. Licensed CC0.

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