# Regulation of GDF11 by extracellular mechanisms

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2022 · $547,365

## Abstract

Project Summary: Growth and Differentiation Factor 11 (GDF11) and GDF8 are two closely related molecules
of the larger TGFβ superfamily. While GDF8 is well known for its role in the regulation of muscle mass, evidence
is now emerging that implicates GDF11 as a factor that has beneficial effects on multiple biological systems.
Both GDF11 and GDF8 are tightly regulated by multiple mechanisms. Each ligand is made as a precursor with
an N-terminal prodomain that remains noncovalently bound to the mature, keeping the signaling component
latent until activated by Tolloid-like proteases. In addition, extracellular antagonists such as Follistatin and GASP
bind and block ligand signaling. We propose that GDF11 and GDF8 are present in the serum in multiple activity
states ranging from a latent form to an activated form. However, studies that investigate how the different activity
states are differentially regulated are limited. We rationalize that a better understanding of these mechanisms
will facilitate efforts to understand the systemic role of GDF11 and GDF8 in human biology and the aging process.
To achieve this objective, we will use a combination of biochemical and molecular approaches coupled with in
vitro and in vivo experiments. Our proposal is centered on three specific aims where we will (1) test the
hypothesis that GDF11 and GDF8 exists in multiple ‘activity’ states that regulate a transition from a latent state
to an active state, (2) test the hypothesis that the ‘net’ GDF11/GDF8 activity in serum decreases with age, and
(3) test the hypothesis that GDF11 signaling and its regulation/extracellular antagonism can be decoupled.
Collectively, these aims will provide a better understanding of the mechanisms of extracellular regulation of
GDF11 and GDF8 and how these potentially change during the aging process. Furthermore, we expect to
produce novel GDF11 and GDF8 molecules that can be used as tools to further probe the mechanisms
associated with GDF11 and aging, and can also be used to restore youthful levels of GDF11 in aged animals.

## Key facts

- **NIH application ID:** 10441552
- **Project number:** 5R01AG072087-03
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** THOMAS B THOMPSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $547,365
- **Award type:** 5
- **Project period:** 2020-09-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10441552

## Citation

> US National Institutes of Health, RePORTER application 10441552, Regulation of GDF11 by extracellular mechanisms (5R01AG072087-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10441552. Licensed CC0.

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