# Outside-in Mechanotransduced Inflammatory Targets

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2021 · $370,355

## Abstract

Abstract
Neutrophils mount an early and critical defense in the innate immune response to
pathogens, but are also associated with chronic inflammatory diseases such as
atherosclerosis, autoimmune disease, and cancer. Recruitment of leukocytes to sites of
acute inflammation is a finely orchestrated process initiated by membrane expression
and functional activation of leukocyte and endothelial cell adhesion molecules (CAMs)
including selectins, integrins, and Ig-super family ligands. A set of unifying themes have
emerged over the tenure of this R01 which provide molecular scale insight into how
PMNs integrate force as a spatio-mechanical cue in the transition from rolling to firm
arrest and transendothelial migration: 1) Selectins are endowed with mechanical and
biochemical properties that allow their dissociation lifetime to increase with the rate of
tensile loading; 2) Shear stress and transmembrane calcium release-activated Ca2+
(CRAC) channels regulate calcium flux which functions to synchronize integrin mediated
arrest and shape orientation under shear; 3) allosteric upregulation in affinity of both
LFA-1 and L-selectin in binding ICAM-1 and E-selectin, respectively, facilitates tensile
force buildup to trigger key outside-in signals that are cooperative during PMN
recruitment. In this competitive renewal we apply innovative vascular mimetic
microfluidic channels combined with real-time immunofluorescence imaging to pursue
the following specific aims: 1) Establish the ligand binding and mechanotransduction
events by which human neutrophils are activated to arrest on E-selectin/ICAM-1 via
signaling through L-selectin. 2) Define the mechanotransduction mechanism by which
LFA-1 bonds to ICAM-1 elicits outside-in signaling via Kindlin-3 and other as yet
unidentified adaptors. 3) Develop and test small molecule antagonists to allosteric
domains that interrupt neutrophil activation and recruitment using vascular mimetic
microfluidic screening technology. Our strategy entails the use of freshly isolated human
neutrophils with the overarching goal of identifying regulatory pathways and molecular
targets for prognosis and treatment of granulocytic inflammatory diseases.
Keywords
Neutrophils, Tensile bond force, Integrins, Selectins, Inflammation, Adhesion, Signaling

## Key facts

- **NIH application ID:** 10190782
- **Project number:** 5R01AI047294-22
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Scott Irwin Simon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $370,355
- **Award type:** 5
- **Project period:** 1999-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10190782

## Citation

> US National Institutes of Health, RePORTER application 10190782, Outside-in Mechanotransduced Inflammatory Targets (5R01AI047294-22). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10190782. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*