# Role of the human gut microbiome in modulating age-associated aortic stiffening.

> **NIH NIH F31** · UNIVERSITY OF COLORADO · 2022 · $39,259

## Abstract

PROJECT SUMMARY/ABSTRACT
The purpose of this F31 application is to provide support for Mr. Nathan Greenberg, a 3rd year graduate
student (1st year PhD student) in Dr. Douglas Seals’ (sponsor) laboratory at the University of Colorado Boulder,
to conduct research and training that will prepare him to become an independent investigator in the field of
translational cardiovascular (CV) aging research aimed at the prevention and treatment of age-related CV
diseases (CVD). He plans to refine research skills currently under development and learn a variety of new
technical, conceptual, and professional skills including working with human biospecimens, using pharmaco-
dissection approaches in cultured aortic rings, conducting biochemical assays, and mastering measurement of
in vivo aortic pulse wave velocity. Gut microbiome composition is uniquely altered with CVD and aging, and
consequent gut-derived changes to the circulating milieu are related to CVD. However, whether these age-
related changes causally increase aortic stiffness is unknown. Thus, the proposed research project seeks to
establish the human gut microbiome as a key modulator of age-related aortic stiffening. Guided by strong
preliminary data, Mr. Greenberg will determine, using innovative “humanized” mouse models:
 Aim 1: If age-related changes in the human gut microbiome directly increase aortic stiffness, accompanied
by: i) increases in circulating lipopolysaccharide (LPS) and flagellin, 2 key components of bacterial cell walls
that can enter circulation; ii) activation of toll-like receptors in circulating immune and/or vascular cells; iii)
increased aortic inflammation and oxidative stress; iv) increased formation of advanced glycation end products;
 Aim 2: If aortic intrinsic mechanical stiffness is altered by the gut-derived “factors” in the circulating blood
(“circulating milieu”) by exposing excised aorta rings to plasma from “humanized” mice;
 Aim 3: The mechanisms by which changes in the circulating milieu induced by the gut microbiome of older
vs. young humans directly increases aortic stiffness using innovative “pharmaco-dissection” approaches.
 This research will be the first to investigate a causal role of the aging human gut microbiome and
microbiome-derived circulating milieu in mediating arterial stiffening. If successful, this work will establish the
human gut microbiome as a therapeutic target for treatment/prevention of age-related arterial stiffening.
Overall, the proposed research has the potential to address two important NHLBI Strategic Vision research
priorities: 1) investigate new pathobiological mechanisms important to the onset of CVD; and 2) identify novel
therapeutic targets to prevent and treat CVD. Dr. Seals is an internationally recognized and NIH-funded
scientist with a strong history of successful mentoring in translational CV research, particularly in “vascular
aging”. Under his supervision and with the guidance of expert co-mentors Drs. Vienna Brunt, an...

## Key facts

- **NIH application ID:** 10464510
- **Project number:** 1F31HL164004-01
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** Nathan Thomas Greenberg
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $39,259
- **Award type:** 1
- **Project period:** 2022-08-12 → 2025-08-11

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10464510

## Citation

> US National Institutes of Health, RePORTER application 10464510, Role of the human gut microbiome in modulating age-associated aortic stiffening. (1F31HL164004-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10464510. Licensed CC0.

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