# Defining nuclear mechanisms for ultrarapid mechanically induced gene expression

> **NIH NIH R01** · CORNELL UNIVERSITY · 2024 · $647,460

## Abstract

Project Summary
Cells in the human body are exposed to a broad range of mechanical forces. Cells respond to such mechanical
stimuli with the expression of specific mechanoresponsive genes, enabling the cells to adapt to their physical
environment. This ‘mechanotransduction’ process is particularly important in tissues subjected to large and
highly variable mechanical stresses, such as skeletal muscle, cardiac muscle, and skin, where impaired
mechanotransduction can lead to muscular dystrophy, heart disease, and other pathologies. Research on
mechanotransduction mechanisms has typically focused on proteins at the cell surface and in the cytoskeleton,
along with the signaling pathways activated by these proteins. Recent studies and our preliminary data using
advanced techniques to detect rapid changes in gene expression, however, found that mechanical stimulation
induces expression of mechanoresponsive genes faster than the time needed for cytoplasmic signaling
cascades to reach the nuclear interior, suggesting the existence of novel, yet to be determined
mechanotransduction mechanisms. The overall objective of this proposal is to identify the mechanism
responsible for this ‘ultra-rapid’ induction of mechanoresponsive genes and to determine the functional
consequences of impaired nuclear mechanotransduction. Given the importance of mechanotransduction in
muscle development, maintenance, and disease, the proposed research will focus on skeletal muscle cells.
Nonetheless, insights gained from this research are expected to be also broadly applicable to many other cell
types. The central hypothesis of this proposal is that the nucleus is not just a receiver of cytoplasmic
mechanotransduction signals, but actively participates in transducing mechanical forces in changes in gene
expression. Supporting this idea, deletion or mutation of nuclear envelope proteins that physically connect the
nucleus to the cytoskeleton, such as lamins and components of the Linker of Nucleoskeleton and Cytoskeleton
(LINC) complex, lead to impaired activation of mechanoresponsive genes and cause various muscle diseases.
Nonetheless, how these proteins, and the nucleus in general, participate in cellular mechanotransduction and
interface with established mechanotransduction pathways remains unresolved. The specific aims of the
proposed work are to (1) determine the molecular mechanisms for the ultra-rapid mechanically induced gene
expression and (2) define the role of nucleo-cytoskeletal force transmission, the LINC complex, and lamins in
the mechanotransduction process in muscle cells. The long-term goal is to understand the fundamental
mechanisms by which cells sense and respond to their physical environment, and to determine the effect of
disease-causing mutations on this process. Gaining better mechanistic insights into how mechanical stimulation
activates mechanoresponsive genes in skeletal muscle is critical to the development of new targeted therapeutic
approaches for d...

## Key facts

- **NIH application ID:** 10972964
- **Project number:** 1R01AR084664-01
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** JOHN T LIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $647,460
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10972964

## Citation

> US National Institutes of Health, RePORTER application 10972964, Defining nuclear mechanisms for ultrarapid mechanically induced gene expression (1R01AR084664-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10972964. Licensed CC0.

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