# Altered Mechanotransduction

> **NIH NIH P01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $438,109

## Abstract

Project Summary
We seek to elucidate the biomechanical mechanisms that control the activation of transforming growth factor
beta (TGFβ), a major mediator in the progression of thoracic aortic aneurysms (TAA). In this PPG application
we have put forward the provocative proposal that cells use the latent form of TGFβ, which resides in the
extracellular matrix (ECM), as a sensor of biomechanical changes. Upon alteration in the surrounding matrix
due to inherent structural mutations or changes in surrounding forces, such as blood pressure, TGFβ is
mobilized to remodel the EMC. We posit that to understand the mechanisms controlling latent TGFβ
mobilization, we must identify the specific individual components of the latent TGFβ complex. We will focus on
the properties of TGFβ in the development of two complementary types of vascular lesions; one involves
mutant mice that have Marfan syndrome (MFS) and die from TAA. The other model employs normal mice
whose aortas have been ligated to increase pressure (coarctation model) that results in rapid vascular
remodeling, which we propose duplicates the early events in pressure-related promotion of TAA. Therefore,
one model represents a genetic defect of the matrix with altered ECM composition, whereas the second model
represents a normal matrix remodeled because of an induced stress. We will in Aim 1 identify the isoform of
TGFβ involved in ECM remodeling and TAA biogenesis in MFS mice (with Projects 1 and Cores B and C). In
Aim 2, we will characterize the species of LTBP involved in MFS and hypertensive mice, matrix remodeling,
and aneurysm formation (with Project 4) and elucidate whether the LTBP acts via TGFβ or by an additional
structural function (with Projects 1 and 4 and Cores B and C). In Aim 3, we will discern whether the ECM of
the MFS cells and animals releases active TGFβ more readily that does normal ECM when placed under
mechanical stress (with Project 3 and Core C) and if changes in the ECM that block TAA formation also affect
TGFβ release (with Projects 1 and 4 and Core C). The information obtained from these experiments will
provide an understanding of how latent TGFβ contributes to TAA and thereby illustrate potential points for the
development of drug therapy.
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## Key facts

- **NIH application ID:** 10136696
- **Project number:** 5P01HL134605-04
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** DANIEL B RIFKIN
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $438,109
- **Award type:** 5
- **Project period:** 2018-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136696

## Citation

> US National Institutes of Health, RePORTER application 10136696, Altered Mechanotransduction (5P01HL134605-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10136696. Licensed CC0.

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