# Role of LINC-mediated Mechanosignaling in MSC Aging

> **NIH NIH R01** · BOISE STATE UNIVERSITY · 2021 · $24,239

## Abstract

PROJECT SUMMARY OF THE PARENT GRANT (R01AG059923)
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 Cytoskeleton (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. We will address our principal hypothesis through two
specific aims, each using 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:** 10237039
- **Project number:** 3R01AG059923-01A1S1
- **Recipient organization:** BOISE STATE UNIVERSITY
- **Principal Investigator:** Gunes Uzer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $24,239
- **Award type:** 3
- **Project period:** 2020-03-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10237039

## Citation

> US National Institutes of Health, RePORTER application 10237039, Role of LINC-mediated Mechanosignaling in MSC Aging (3R01AG059923-01A1S1). Retrieved via AI Analytics 2026-08-03 from https://api.ai-analytics.org/grant/nih/10237039. Licensed CC0.

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