# Cell junction and nuclear forces as mediators of epithelial cell homeostasis

> **NIH NIH R35** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $364,687

## Abstract

Epithelial cells, which line both the inside cavities and outside of the body, exist in tissues as monolayers,
multilayers of cells, and three dimensional tube/duct structures. Proper formation and homeostasis of the
epithelium is critical for tissue and organ function; dysregulation of the epithelium is associated with epithelial
barrier loss (including sepsis), defective wound healing, and development and progression of cancer. Although
mechanical forces on epithelial cells have been shown to influence cell organization, proliferation, and
migration, it is not known the mechanisms by which cells respond to force. This proposal examines the role of
force across proteins in both cell-cell junctions and the nuclear linker of nucleoskeleton to cytoskeleton (LINC)
complex as mediators of epithelial homeostasis. Strong cell-cell junctions are critical to the integrity of the
epithelium, including cell cohesion, barrier function, and ability to resist mechanical stress. Loss of junctions is
associated with epithelial dysfunction including inflammatory-induced increases in permeability and epithelial to
mesenchymal transition (EMT). Although formation cell-cell adhesions have been shown to be critical
regulators of cell proliferation, migration, and tissue organization, very little is known how cell-cell junction
forces contribute to these processes. In addition to altering junction forces, externally applied forces are likely
transmitted inside the cell, across the cytoskeleton, and onto organelles. The nucleus, which is physically
connected to the cytoskeleton by the LINC complex, is likely affected by external forces. Nuclear forces have
been suggested to regulate nuclear geometry and nuclear positioning, both of which are altered in a variety of
diseases, including cancer. The major research goals of this MIRA proposal are to examine how forces across
cell-cell junction proteins and the nuclear LINC complex regulate epithelial proliferation, migration, junction
stability, and 3D organization. Novel FRET-based tension biosensors will be used to directly measure forces
across tight junctions, adherens junctions, and desmosomes at cell-cell junctions and specific isoforms of
nesprin at the LINC complex. Treatments or mutants for which junction or nuclear force is perturbed will be
used to assess the causal nature of force in regulation of the epithelium. An additional goal of this proposal is
to identify the relationship between forces across cell-cell junctions, cell-matrix adhesions, and the nuclear
LINC complex, identifying how forces are transmitted from one region of the cell to another. This
comprehensive study of cell-cell, cell-matrix, and nuclear forces will greatly advance the understanding of
epithelial homeostasis, which includes the processes of wound repair, inflammation, and epithelial tissue
development and organization, as well as epithelial diseases, including cancer, fibrosis, and chronic
inflammation. Junction and nuclear forces ma...

## Key facts

- **NIH application ID:** 9962447
- **Project number:** 5R35GM119617-05
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Daniel E Conway
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $364,687
- **Award type:** 5
- **Project period:** 2016-09-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962447

## Citation

> US National Institutes of Health, RePORTER application 9962447, Cell junction and nuclear forces as mediators of epithelial cell homeostasis (5R35GM119617-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9962447. Licensed CC0.

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