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Genetic analysis of intrinsic sensory neuron function in the enteric neural circuits

Award Number: R01DK134773
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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SUMMARY The gastrointestinal (GI) tract is the only abdominal organ that has evolved with its own enteric nervous system (ENS) fully contained within the gut wall, also known as the “second brain” in the gut. Our long-term goal is to understand how the intrinsic primary sensory neurons (IPANs) in the ENS detect and respond to both physical and chemical cues in the gut lumen and control propulsion of content in the colon. Although known for about 25 years, the IPANs are still a subset of the most mysterious neurons in the ENS because how they participate in coordinated muscle movements (motility), regulate immune cell function (immunity) and maintain integrity of intestinal barrier is not completely understood. Equally as mysterious is whether the IPANs can fulfil the function as a “pattern generator” and can control the rhythmicity of cyclical propagating contractions along the colon. This is largely due to a lack of tools that can be used to selectively manipulate the excitability of specific classes of enteric neurons and any drugs that have been tried to stimulate or block activity in IPANs will likely act on many other types of neurons (or non-neuronal cells), making interpretation of the results unclear. In pilot studies, we have generated critical resources enabling us to identify and selectively targeting the ß- CGRP-expressing (ß-CGRP+) IPANs. By using these unique resources, we will be able to ask important questions regarding the roles of the ß-CGRP+ IPANs in the ENS: What role the ß-CGRP+ IPANs have in the propagation of neural activity along the gut? Are these IPANs activated by both mechanical and chemical cues in the gut lumen? Can these IPANs serve as cellular sensors for distinct microbiota-derived metabolites? This proposal represents a major technical advance by using cutting-edge neurogenetic approaches which make it possible to genetically target and determine the functionality of the ß-CGRP+ IPANs in the ENS both ex vivo and in vivo, providing the first insights into how selective activation and inhibition of the ß-CGRP+ IPANs in the ENS affects GI-motility. This information will advance our understanding of the inner workings of the ENS and shed new insights on the development of novel strategies for the treatment of motility-related GI disorders by targeting the IPANs in the ENS.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $552,735 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/20/2023	NEW	$552,735


Grand Total All Awards = $552,735

Sum of Action Amount is $552,735;

Grand Total = $552,735

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Genetic analysis of intrinsic sensory neuron function in the enteric neural circuits

Award Number: R01DK134773

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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