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Genetic and extrinsic mechanisms governing early enteric nervous system development

Award Number: R01DK124804
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/27/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Genetic and extrinsic mechanisms governing early enteric nervous system development - Resident between the muscle walls of the entire gastrointestinal (GI) tract, the enteric nervous system (ENS) consists of a series of interconnected neurons and glia, numbered in the hundreds of millions. The ENS controls essential gut functions, such as peristalsis, water balance and intestinal barrier homeostasis. The ENS is derived from enteric neural progenitors (ENPs) that migrate into the developing gut tube during embryogenesis and differentiate into enteric neurons or glia. Disruption in ENS formation results in the congenital condition Hirschsprung disease (HSCR), in which variable regions of the GI lack ENS—the most common form of HSCR presents along the distal colon, also known as colonic aganglionosis. The underlying cellular mechanisms that ENPs utilize to migrate into and spatially position along the gut tube, as well as genetic programs they execute to differentiate into enteric neurons have not been well studied in vivo, therefore limiting our knowledge of how the ENS manifests. The overall goal is to expand foundational knowledge of the genes utilized to execute the complex mechanisms necessary for ENS formation, with an eye for informing downstream translational therapeutic studies. In this proposal, we utilize zebrafish embryos due to their genetic conservation with humans, the ease of viewing their external development and for their optical transparency. Building off of single-cell transcriptomic data sets generated from ENP cells collected during their early neurogenesis along the gut tube, Aim 1 will examine a hypothesis that the spatial arrangement of newly uncovered ENP transcriptional subpopulations predict future enteric neuron placement and terminal differentiation along the gut tube. In agreement with and extending observations in mammalian models, we have recently discovered that Retinoic Acid (RA) signaling is critical globally during early steps of zebrafish ENS development; however, how RA signaling autonomously influences ENS ontogenesis in vivo is not well understood in any system to date. Aim 2 will investigate a hypothesis that the RA pathway autonomously controls ENP differentiation states and migration patterns along the gut tube using cutting edge single-cell transcriptomics, optogenetics and in vivo imaging. We will also test a mechanistic model in Aim 2 that candidate transcription factors function intrinsically downstream of RA in ENPs to govern ENS formation, thereby expanding our understanding of the ENS gene regulatory network. Aim 3 will use genetic modulation of the cell cycle, quantitative in vivo imaging and cell tracking test a cellular mechanistic model that ENPs couple proliferation with migration to dictate proper enteric neuron patterning in the gut downstream of the RA pathway. The results of these aims will significantly increase our knowledge of the genetic, molecular and cellular underpinnings of ENP development and early ENS creation and they will provide a new mechanistic framework for studying these developmentally important cells in vivo.


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: 2025 ( Subtotal = $358,259 )
2025	2025	WILLIAM MARSH RICE UNIVERSITY	6100 MAIN ST	HOUSTON	TX	77005	HARRIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	2/25/2025	NON-COMPETING CONTINUATION	$358,259
														Subtotal = $358,259

Issue Date FY: 2024 ( Subtotal = $382,143 )
2024	2024	WILLIAM MARSH RICE UNIVERSITY	6100 MAIN ST	HOUSTON	TX	77005	HARRIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	5/10/2024	NON-COMPETING CONTINUATION	$23,884
2024	2024	WILLIAM MARSH RICE UNIVERSITY	6100 MAIN ST	HOUSTON	TX	77005	HARRIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/15/2024	NON-COMPETING CONTINUATION	$358,259
														Subtotal = $382,143

Issue Date FY: 2023 ( Subtotal = $398,066 )
2023	2023	WILLIAM MARSH RICE UNIVERSITY	6100 MAIN ST	HOUSTON	TX	77005	HARRIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/16/2023	NON-COMPETING CONTINUATION	$398,066
														Subtotal = $398,066

Issue Date FY: 2022 ( Subtotal = $395,311 )
2022	2022	WILLIAM MARSH RICE UNIVERSITY	6100 MAIN ST	HOUSTON	TX	77005	HARRIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/1/2022	NON-COMPETING CONTINUATION	$355,778
2022	2022	WILLIAM MARSH RICE UNIVERSITY	6100 MAIN ST	HOUSTON	TX	77005	HARRIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	3/29/2022	NON-COMPETING CONTINUATION	$39,533
														Subtotal = $395,311

Issue Date FY: 2021 ( Subtotal = $407,706 )
2021	2021	WILLIAM MARSH RICE UNIVERSITY	6100 MAIN ST	HOUSTON	TX	77005	HARRIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/26/2021	NEW	$407,706
														Subtotal = $407,706

Grand Total All Awards = $1,941,485

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Genetic and extrinsic mechanisms governing early enteric nervous system development

Award Number: R01DK124804

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/27/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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