# Molecular mechanisms of sensory transduction in the gut

> **NIH NIH R00** · HARVARD UNIVERSITY · 2020 · $249,000

## Abstract

Project Summary
Specialized sensory organs contain functionally dedicated cell types that detect relevant stimuli and relay
information to the nervous system. In this proposal, we ask if this concept also pertains to the gut epithelium,
which constitutes one of the largest exposed surface areas of the human body and is in contact with a diverse
chemical environment. Indeed, numerous chemical changes in the gut lumen have been associated with
visceral pain, including irritants, endogenous inflammatory molecules, and microbiota-produced metabolites.
Despite growing interest in the gut-neural axis, relatively little is known about molecular mechanisms
underlying chemosensory transduction by the gut epithelium, or how this information is transmitted to the
nervous system. Serotonergic enterochromaffin (EC) cells are rare, but highly specialized entities within the gut
epithelium that have been implicated in visceral pain but have eluded detailed characterization due, in part, to
their paucity. To circumvent these limitations, we generated intestinal organoids from a transgenic mouse in
which EC cells are marked with a fluorophore, enabling us to carry out detailed single-cell profiling of these
cells in the context of a native tissue environment. Our preliminary data show that these cells are electrically
excitable, polymodal chemosensory detectors of the gut that engage in direct synaptic interactions with
sensory nerve fibers to transduce information about intestinal state. In these proposed studies, we will define
intrinsic EC cell electrophysiological properties, chemosensory transduction mechanisms, and serotonin
release mechanisms (Aim 1) and utilize this information to investigate the physiological effects of EC activation
on and associated neural pathways (Aim 2). Finally, we will obtain genetic access to EC cells and use
chemogenetic tools to examine their contribution to visceral pain (Aim 3). This work will elucidate EC cell
chemosensory mechanisms and examine their role in visceral pain to provide a mechanistic foundation for
understanding how the gut epithelium communicates with the nervous system. This molecular foundation is
critical for uncovering basic mechanisms that contribute to pathophysiology underlying visceral pain disorders,
such as irritable bowel syndrome.
Proposed experimental approaches for this award combine my expertise in cellular physiology and biophysics
with new training in genetics and GI physiology, allowing me to address significant biological questions and
identify novel molecular mechanisms. A unique mentorship team with extensive experience in signal
transduction, pain, synaptic physiology, and GI physiology will provide expert guidance and an ideal
environment for proposed scientific and professional development. Thus, the training supported by this award
will be critical to establishing a unique and important independent research program in neuroscience and
gastrointestinal physiology.

## Key facts

- **NIH application ID:** 9983664
- **Project number:** 5R00DK115879-04
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** Nicholas Bellono
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $249,000
- **Award type:** 5
- **Project period:** 2018-09-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983664

## Citation

> US National Institutes of Health, RePORTER application 9983664, Molecular mechanisms of sensory transduction in the gut (5R00DK115879-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9983664. Licensed CC0.

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