# Developing a microphysiological system of a humanized Gut-Brain-Axis for age-associated transmissible neuropathologies

> **NIH NIH R21** · JOHNS HOPKINS UNIVERSITY · 2022 · $216,406

## Abstract

Project Summary
This project is focused on engineering a novel innervated microphysiological system (MPS) of the young and
aged brain-gut axis (GBA) in health and disease. The GBA is comprised of neural circuits where the vagus nerve
connects enteric nervous system (ENS) neurons that reside in the gut to central nervous system (CNS) neurons,
thus allowing for bi-directional communication. There is a need for simplified models of the neural pathways from
gut-to-brain where the underlying mechanisms of action in health and disease are not well understood. The
vagus nerve, predominantly sensory neurons located in the Nodose Ganglia, transduces dietary cues and CNS
function by gut bacteria and has been implicated in neurotransmittable neurodegenerative diseases such as
Parkinson’s Disease (PD). Thus, an MPS that captures key components of the human brain-gut axis (GBA),
including primary central hind brain neurons, vagal neurons, and enteric neurons, would be a valuable tool for
understanding and manipulating pathway function in young and aged tissue and for advancing discovery and
therapies via neuromodulation. The approach here describes validation of a laser-fabricated, cut & assembled
MPS towards a humanized GBA. Our multidisciplinary team has worked together to (1) establish a prototype
GBA-MPS, (2) validate 3D neural compartments within assembled MPS, (3) demonstrate primary human
neurosphere sourcing, and (4) create a transgenic model of gut innervating nodose neurons. Two aims will be
pursued. Aim 1 will engineer an MPS with real-time sensing of GBA function via live electrophysiology and
imaging, followed by time-course and end point characterization of neural function in young and aged populations
compared to static and monocultures to ensure appropriate fate and phenotype. Aim 2 will validate the utility of
the platform to create a disease model PD phenotype by pre formed fibrils (PFFs) in the enteric neurons of the
young and aged MPS, and harness photostimulation of opsin expressing transgeneic nodose neurons, the circuit
lynchpin, to evalutate neuromodulation as a method to slow PD spread from the gut to the brain compartment.
Successful completion of the first ever MPS that simulates human GBA will accelerate the mechanistic study of
brain-gut communication in health and disease and advance therapeutic target discovery by enabling analysis
of neural biology and neurodegenerative disorders an accessible and instrumented MPS platform.

## Key facts

- **NIH application ID:** 10450941
- **Project number:** 1R21AG072107-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Abigail Nelson Koppes
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $216,406
- **Award type:** 1
- **Project period:** 2022-09-30 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10450941

## Citation

> US National Institutes of Health, RePORTER application 10450941, Developing a microphysiological system of a humanized Gut-Brain-Axis for age-associated transmissible neuropathologies (1R21AG072107-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10450941. Licensed CC0.

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