ChE Professors Win NIH Trailblazer New/Early Career Investigator Award
Chemical Engineering Assistant Professors Abigail and Ryan Koppes are on a mission to improve our understanding of how the brain and gut communicate with each other. The team will pursue their research on the subject under a three-year, $632,000 grant— the Trailblazer New/Early Career Investigator R21 Award—from the National Institutes of Health (NIH) National Institute of Biomedical Imaging and Bioengineering.
A new NIH program launched last year, the “Trailblazer” award is designed for pre-tenured academic professionals who have not yet won NIH grants as principal investigators. Abigail and Ryan Koppes are early career professionals, having joined the Northeastern University faculty in 2014 and 2015, respectively, after earning their PhDs in biomedical engineering at RPI. The award is aimed at jumpstarting NIH funding for researchers doing high-risk, high-impact projects that may be technology design-directed, discovery-driven, or hypothesis-driven.
Under the grant, the Koppes will create a benchtop model or platform called “body on a chip” to mimic certain aspects of the brain and gut. Their research will focus on the enteric nervous system—the system associated with the ‘butterflies in the stomach’ feeling. “The system controls how the body absorbs nutrients and is viewed as a gatekeeper to regulate gut function,” says Abigail. “We want to model that system to understand how it is controlled and what cellular players are involved from the nervous system.”
Developing a humanized system
The team will work with researchers at Boston Children’s Hospital and Harvard Medical School—under the direction of Dr. David Breault, an endocrinologist and principal faculty of Harvard’s Stem Cell Institute—to develop a “humanized” system using primary sourced cells, creating a platform that is more representative of native human states.
The team’s research will address the as-yet unproven theory that it may be possible to harness the nervous system to reduce inflammation present in diseases such as Irritable Bowel Syndrome. “We hope to use the new field of bioelectronic medicine, which is using electrical stimulation to turn cells on or off to reduce inflammation,” says Abigail. “Ultimately our goal is to use the body’s own neural network to mitigate inflammation.”
In addition to improving our understanding of how the nervous system and gut regulate each other’s function, the team hopes to translate the technology they are developing to other systems, for example, the blood/brain barrier, to enable researchers to find new pathways to drug therapies.
Converging interests and expertise
The NIH award represents a convergence of the Koppes’ interests and expertise, according to Ryan who is a specialist in brain-machine interfaces, the development of tools to interface with nerves. Abigail, whose PhD thesis focused on neural tissue engineering, “comes at this from the ‘gut’ side and I come at it from the ‘tech’ side,” he says. “We put our two interests together to ask bigger questions, to collaborate on this project. We started in different areas of biomedical science to make a humanized platform.”
Abigail’s post-doctoral work with ChE Professor Rebecca Carrier on gut function sparked her interest in the brain-gut connection as did her collaboration in microfluidics with ChE Professor Shashi Murthy. They will continue to approach this work from a collaborative perspective, with help from three students led by ChE PhD candidate Sanjin Hosic, co-advised by Abigail and Murthy.
“There’s a big link between emotion, anxiety and our digestive system, especially the gut, and we’re only starting to be able to understand it,” says Ryan. “This platform may be able to answer a few of those questions on why our gut health impacts our mood and vice versa.”
Abstract Source: NIH
Project Summary This project is focused on developing a novel in vitro platform for studying the impact of the enteric nervous system on epithelial phenotype. There is a need for a simplified model of the human gut-enteric axis, as a clear connection exists between gut and neural health and dysfunction, but the underlying regulatory mechanisms are not well understood. The enteric nervous system is known to have tremendous impact on gut homeostasis, especially the potential for inducing an anti-inflammatory response with vagus nerve stimulation. However, due to the non-specificity of bioelectric vagal targeting and the limitations of probing innervated organs in vivo, clinically relevant stimulation regimes for the gut have yet to be identified. Human intestinal epithelial cells express receptors that are specific for enteric neurotransmitters, such as acetylcholine, which may be activated during electrical stimulation leading to an anti-inflammatory phenotype. Thus, a microphysiological system that recapitulates key components of the human gut-enteric-axis, including shear flow, oxygen saturation, bioelectric stimulation, primary human epithelium, and primary human enteric neurons would be a valuable tool for advancing scientific discovery, healthcare, compound screening, and biomedical research. Current organ-chips generally utilize specialized equipment and microfabrication techniques for platform development, limiting dissemination, as well as do not include primary human small intestinal epithelium or enteric neurons. The approach here describes the development of a laser-fabricated, cut and assembled body-chip for a humanized gut-enteric axis (hGEA). The team has worked together to establish a prototype hGEA and establish primary enteric and epithelial cultures, and thus have demonstrated their complimentary teaming ability towards product development. Two parallel and synergistic aims will be pursued, with platform development in Aim 1 utilizing laser machining and assembly to fabricate the hGEA with microelectrode array electrophysiology capabilities, followed by characterization of neural and epithelial responses on chip compared to static transwell controls over 0-14 days, and lastly oxygen and shear flow modeling to recapitulate physiological conditions. Aim 2 will investigate the impact of electrical stimulation of enteric neurons to modulate a chemically induced inflammatory phenotype in the primary human epithelium, and characterize especially (but not limited to) nicotinic acetylcholine receptor proteins, trans epithelial electrical resistance (TEER), enzyme and mucus production, and cytokine release as markers of epithelial health. Experiments will be benchmarked to conventional Caco-2 models and static controls. The successful completion of the first ever in-vitro human GEA will accelerate the mechanistic study of gut disease, including inflammatory disorders, and advance therapeutic target discovery by enabling analysis on an accessible and cost-effective, laser cut and assembled microphysiological platform.