Genetic and molecular perturbations of enteric nervous system architecture in gastrointestinal disease

The National Institute of Diabetes and Digestive and Kidney Diseases awarded The Leland Stanford Junior University $784,530 on September 1, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to characterize the cellular and molecular architecture of the enteric nervous system under homeostatic and perturbed conditions.

The recipient will develop and apply an integrated spatial multi-omics analytical workflow to study the enteric nervous system's organization and function in gastrointestinal health and disease. The project employs a sample preparation technique that preserves enteric nervous system structure and enables simultaneous analysis of the tissue's cellular composition, molecular signaling, and spatial organization, addressing a fundamental limitation in enteric nervous system research: the intricate anatomical organization of the nervous system as it extends along the entire length of the gastrointestinal tract. The work focuses particularly on intestinal inflammation as a perturbed condition model.

Performance takes place in Palo Alto, California, with a period of performance from September 1, 2026, through June 30, 2031. The award is structured as a Project Grant, the standard assistance type for individual investigator-initiated biomedical research supported by NIH.

Abstract

The enteric nervous system (ENS) is emerging as a critical regulator of intestinal physiology, immunity, and metabolism in health and disease. IT shares several features with the central nervous system (CNS), including the use of similar neurotransmitters and the basic principles of neuron-neuron and neuron-glia interactions. However, in contrast to the CNS, the functional properties and architectural design principles of the ENS remain largely uncharacterized. The overarching goal of this proposal is to introduce a transformative technological approach to the study of the ENS and its function in gastrointestinal health and disease. A major roadblock in the study of the ENS is its intricate anatomical organization as an organ-intrinsic nervous system that extends along the entire length of the gastrointestinal tract, which has made IT much more difficult to study its molecular architecture compared to neurons in the brain. As a result, many of the most fundamental questions in ENS biology remain unsolved. My group has recently developed a technological workflow that allow US to overcome these limitations in the study of the ENS. This strategy takes advantage of a unique sample preparation technique that preserves the structure of the ENS and enables integrated spatial multi-omics analysis of the tissue. We propose to apply this enabling technology to characterizing the cellular and molecular architecture of the ENS under homeostatic and perturbed conditions, particularly during intestinal inflammation. Based on its versatility, ease of implementation, and ability to yield transformative insights into ENS function, we expect this technological workflow to become widely adapted by the community and to significantly advance our understanding of this organ-intrinsic nervous system that its impact on gastrointestinal function and disease.