# To study how progerin affects endothelial alignment and migration under flow using a continuum-tensegrity based computational model

> **NIH NIH R03** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $79,250

## Abstract

PROJECT SUMMARY/ABSTRACT
 The human aging process increases the risk of cancer and cardiovascular diseases that together account
for the most death in United States. Nuclear lamina, present in most cell nuclei, is implicated in the aging
process. Made of type V intermediate filaments called lamin, lamina sits underneath the nuclear envelope,
provides structural support, and is involved in chromatin organization and other regulatory pathways. Mutations
in lamin, lamin-associated proteins, and other nuclear envelope proteins account for a range of human
diseases called laminopathies. Among them is Hutchinson-Gilford progeria syndrome (HGPS), a rare
premature aging disorder caused by a point mutation in lamin A/C gene that results in a truncated lamin mutant
known as progerin. Progerin is responsible for the characteristics of old age in children with HGPS, who
develop atherosclerosis aggressively and usually die from heart attack or stroke in their teens. Interestingly,
progerin is also found in normal people, and increases with age. Vasculature of HGPS patients share many
similarities with that of old people. Defective nuclear lamina in aged cells resemble nuclei of HGPS cells, with
the characteristic distorted nuclear shape. While progerin could be a novel contributor to vascular aging, its
role in the mechano-biology of endothelial cells in HGPS patients or older adults is not understood.
 Our long term goal is to investigate the effect of progerin in human endothelial mechano-biology under
shear stress. In this project, we focus on how progerin affects cell alignment and migration in wound recovery
under flow. Our overall hypothesis is that progerin-expressing endothelial nuclei have compromised responses
to shear stress. Using both computational as well as cell based approaches, this project will evaluate the
effects of shear stress on endothelial cell alignment and migration in wound recovery (Aim 1); and begin to
develop a hybrid continuum-tensegrity computational model of endothelial cell under flow (Aim 2).
 Based on previous studies and preliminary data, we hypothesize that progerin-expressing endothelial
nuclei have compromised ability to sense shear stress and as a result, cells will fail to align properly under flow
and have decreased wound recovery (Aim 1). We also hypothesize that nucleus and MTOC orient under shear
stress in a way to minimize internal stress due to fluid flow and that this process is disrupted in cells with
progerin. To test this hypothesis, we will develop a computation model of endothelial cell under shear stress
using a hybrid approach that integrates continuum and structural models, a cellular fluid-structure interaction
model with cytoskeletal elements (Aim 2). Simulation results will be correlated with experimental results to
analyze nuclear stress under flow. A complete 3D model will help delineate how shear stress is transduced to
the nucleus, especially in diseases that impact nuclear mechanics. This study ...

## Key facts

- **NIH application ID:** 9984928
- **Project number:** 5R03AG063150-02
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Julie Y. Ji
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $79,250
- **Award type:** 5
- **Project period:** 2019-08-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9984928

## Citation

> US National Institutes of Health, RePORTER application 9984928, To study how progerin affects endothelial alignment and migration under flow using a continuum-tensegrity based computational model (5R03AG063150-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9984928. Licensed CC0.

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