# Role of LINC-mediated Mechanosignaling in MSC Aging

> **NIH NIH R01** · BOISE STATE UNIVERSITY · 2023 · $280,602

## Abstract

Project Summary
 Mesenchymal stem cells (MSC) in bone marrow provide regenerative capacity for bone, replacing and
reinforcing the skeleton at load bearing sites. When we age or in prolonged bedrest, MSCs lose their
regenerative potential, often measured by their proliferative and differentiation capacity. This loss of MSC
health causes osteoporosis and delayed healing, ultimately resulting in decreased quality of life and
increased medical costs. A fundamental knowledge gap preventing effective therapies in aging and MSC
related regenerative medicine is how aging and bedrest impedes MSC health.
 The nucleus, central to all cellular activity, relies on both mechanical input as well as its molecular
transducers to regulate intra-nuclear chromatin organization that ultimately determine cell function and
fate. Thus, failure to transmit this information to the nucleus would lead to the breakdown of these
processes. Here, we ask if aging is a process that limits information flow into the nucleus, ultimately
diminishing its organizational capacity and responsiveness to outside stimuli. As we will show, disabling
the mechanical connection between cytoskeleton and nucleus facilitated by Linker of Nucleoskeleton and
Nucleoskeleton (LINC) complexes, impairs mechanosensitivity by affecting βcatenin and YAP/TAZ
signaling. This leads to decreased proliferation and differentiation of mesenchymal stem cells.
Our principal hypothesis is that loss of LINC-connectivity significantly contributes to MSC aging by
 disrupting nuclear mechanotransduction.
 Through this revision submitted in response to [PA16-442] - Changes in Cellular Architecture
During Aging (R01), we will address our principal hypothesis through two specific aims, each using a
distinct hypotheses to examine how inhibiting LINC complex function as well as how aging related loss
of LINC complex limits MSC mechanosignaling of known mechanotransducers βcatenin and YAP/TAZ.
We will further determine the force-induced mechanisms of how sustained physical activity protects LINC
complex expression to augment MSC and bone mechanosignaling within the context of aging.
If successful, we will establish, for the first time, a mechanistic understanding of how loss of LINC complex
drives decreased mechanosensory capability in aging. Completion of these aims will provide research
communities with (1) efficacy of LIV based regenerative modalities that improve LINC-mediated
mechanosignaling and (2) foundational structure-function relationship data in healthy and aged stem
cells.

## Key facts

- **NIH application ID:** 10559581
- **Project number:** 5R01AG059923-04
- **Recipient organization:** BOISE STATE UNIVERSITY
- **Principal Investigator:** Gunes Uzer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $280,602
- **Award type:** 5
- **Project period:** 2020-03-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10559581

## Citation

> US National Institutes of Health, RePORTER application 10559581, Role of LINC-mediated Mechanosignaling in MSC Aging (5R01AG059923-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10559581. Licensed CC0.

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