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Investigation of Enteric Nervous System Regeneration in Zebrafish Using a Cell Ablation System with Spatio-Temporal Control

Award Number: R21NS123629
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Investigation of Enteric Nervous System Regeneration in Zebrafish Using a Cell Ablation System with Spatio-Temporal Control - This project aims to determine the regenerative capacity of the enteric nervous system (ENS) and identify the cellular and molecular mechanisms that control ENS regeneration. The ENS provides the intrinsic innervation of the gastrointestinal (GI) tract and controls all essential gut functions including motility. Deficits in ENS neuron abundance are associated with a wide range of disorders characterized by GI dysfunction, debilitating symptoms, and reduced quality of life. To date, ENS disorders can only be treated symptomatically or by surgical removal of the affected area. A promising avenue to treat lost ENS cells is to stimulate local stem cells to regenerate missing ENS neurons. However, there is a significant gap in knowledge regarding the signals and cell lineages necessary for successful ENS regeneration. To address this knowledge gap, we need to establish an experimentally tractable animal model system that displays robust ENS regeneration including recovery of gut functions. In mammals, the ENS only partially reinnervates and recovers neurons after injury. Unlike mammals, the zebrafish ENS regenerates ENS injury after focal ablation of a small number of ENS neurons. However, whether zebrafish can repair extensive ENS injuries in all parts of the gut, and the extent of functional recovery following regeneration is not known. Furthermore, we know very little about the molecular cues, cell biological processes, and cell lineage composition that underlie ENS regeneration. Thus, there is a critical need to establish the cellular and molecular mechanisms as well as the cell lineage decisions that guide ENS regeneration in zebrafish. Establishing an animal model system of robust ENS regeneration will pave the way for our long-term goal to identify the genes and gene regulatory networks necessary and sufficient for successful ENS regeneration. This proposal tests the central hypothesis that the zebrafish gut environment allows enteric stem cell activation to generate lost ENS neurons in two Aims: (1) establish the regenerative ability of the zebrafish ENS; (2) identify cell populations, spatio-temporal gene expression dynamics, and cell lineages that drive neuronal regeneration after cell ablation. Aim 1 utilizes a genetic- chemical ablation system for precise spatio-temporal control of cell loss and high-resolution whole-gut imaging to analyze functional recovery. Aim 2 uses single-cell RNA-seq (scRNA-seq) to identify the cellular and molecular profiles of the cell types and lineages that drive the regenerative response. This proposal is innovative, as it will capitalize on the precision of the genetic-chemical cell ablation system and the exceptional cellular and molecular resolution of scRNA-seq to establish an animal model system of robust ENS regeneration and thereby open new horizons for the study of nervous system regeneration. This work is significant, as it will provide the necessary foundation for understanding which molecular cues and cellular responses promote ENS regeneration and how such factors can be applied to enhance human ENS regeneration to treat neurological diseases of the gut.


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: 2024 ( Subtotal = $0 )
2024	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/16/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $104,763 )
2023	2023	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/30/2023	SUPPLEMENT FOR EXPANSION	$104,763
														Subtotal = $104,763

Issue Date FY: 2022 ( Subtotal = $439,408 )
2022	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/7/2022	NEW	$439,408
														Subtotal = $439,408

Grand Total All Awards = $544,171

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Investigation of Enteric Nervous System Regeneration in Zebrafish Using a Cell Ablation System with Spatio-Temporal Control

Award Number: R21NS123629

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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