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Regulation of enteric motor neurocircuits by enteric glia in health and disease

Award Number: R01DK103723
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: 07/15/2015
PERIOD OF PERFORMANCE END DATE: 04/30/2030

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Regulation of enteric motor neurocircuits by enteric glia in health and disease - PROJECT SUMMARY Experiencing gut inflammation imparts long-lasting effects on the neural control of gut motility that contribute to persistent gut motility issues in irritable bowel syndrome and inflammatory bowel disease. Intestinal motility is governed by neural circuits in the enteric nervous system (ENS) and changes in how enteric motility neurocircuits function play a central role in post-inflammatory gut dysfunction. The underlying mechanisms remain poorly understood. Enteric glia surround enteric neurons and regulate gut motility through effects on neuronal excitability and neuroinflammation. The overall goal of this proposal is to define how specialized interactions between enteric glia and neurons regulate motility and how alterations in those mechanisms contribute to post-inflammatory gut dysfunction. This proposal tests the central hypothesis that enteric gliotransmission regulates gut motor function through subtype-specific effects on enteric neurons and that inflammation provokes a switch in gliotransmission that disrupts neural control of gut motor functions. This dual hypothesis will be tested in two specific aims that utilize neuron subtype-targeted genetically encoded calcium indicators and glial chemogenetic actuators to study how glia modulate specific types of enteric neurons, and a post-inflammatory model of enteric neuroplasticity to study how glia contribute to ENS hyperexcitability following inflammation. Aim 1 will study the cell- and synapse-specificity of gliotransmission in propulsive motility neurocircuits by testing the hypothesis that enteric gliotransmission regulates propulsive motility through subtype-specific effects on enteric neurons. Aim 1.1 will involve cellular imaging experiments that combine neuron subtype-targeted GCaMP expression with glial cell activation using chemogenetics to test the hypothesis that enteric gliotransmission preferentially influences interneurons in propulsive motility reflexes. Aim 1.2 will use the DNBS colitis model to understand how changes to the nature and specificity of gliotransmission promote ENS hyperactivity following inflammation. Aim 2 will study how glia regulate colonic motor complex behavior by coordinating excitatory neurons. Aim 2.1 will use calcium imaging experiments in mice that express GCaMP in cholinergic neurons and chemogenetic actuators in glia to test the hypothesis that enteric gliotransmission mediated by S100B regulates rhythmic cholinergic neuron activity underlying colonic motor complexes. Aim 2.2 will test the hypothesis that a failure of this glial regulatory system contributes to uncoordinated colonic motor complex function following inflammation through effects on neuron and glial excitability. The results of this study will provide novel insight into glial mechanisms that regulate ENS circuits. A better understanding of the glial mechanisms that regulate motility will facilitate developing new therapeutics that modify ENS command of gut motility.


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: 2026 ( Subtotal = $502,932 )
2026	2026	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 360	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	12	4/1/2026	NON-COMPETING CONTINUATION	$502,932
2026	2024	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 360	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	3/17/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $502,932

Issue Date FY: 2025 ( Subtotal = $517,932 )
2025	2025	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	11	7/1/2025	COMPETING CONTINUATION	$517,932
2025	2024	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	6/23/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $517,932

Issue Date FY: 2024 ( Subtotal = $330,478 )
2024	2024	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	6/26/2024	NON-COMPETING CONTINUATION	$330,478
														Subtotal = $330,478

Issue Date FY: 2023 ( Subtotal = $344,551 )
2023	2023	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	7/13/2023	NON-COMPETING CONTINUATION	$344,551
														Subtotal = $344,551

Issue Date FY: 2022 ( Subtotal = $344,842 )
2022	2022	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	8	6/29/2022	NON-COMPETING CONTINUATION	$344,842
2022	2020	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	10/29/2021	COMPETING CONTINUATION	$37
2022	2019	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	10/29/2021	SUPPLEMENT FOR EXPANSION	-$37
														Subtotal = $344,842

Issue Date FY: 2021 ( Subtotal = $345,122 )
2021	2021	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	6/23/2021	NON-COMPETING CONTINUATION	$345,122
2021	2020	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	6	8/8/2021	COMPETING CONTINUATION	$35,073
2021	2019	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	8/8/2021	SUPPLEMENT FOR EXPANSION	-$35,073
														Subtotal = $345,122

Issue Date FY: 2020 ( Subtotal = $345,391 )
2020	2020	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	6	7/8/2020	COMPETING CONTINUATION	$345,391
2020	2019	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	6/30/2020	SUPPLEMENT FOR EXPANSION	$0
2020	2019	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	6/30/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $345,391

Issue Date FY: 2019 ( Subtotal = $433,897 )
2019	2019	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	7/25/2019	SUPPLEMENT FOR EXPANSION	$72,885
2019	2019	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	4/16/2019	NON-COMPETING CONTINUATION	$361,012
														Subtotal = $433,897

Issue Date FY: 2018 ( Subtotal = $361,012 )
2018	2018	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	5/1/2018	NON-COMPETING CONTINUATION	$361,012
														Subtotal = $361,012

Issue Date FY: 2017 ( Subtotal = $424,066 )
2017	2017	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	6/15/2017	NON-COMPETING CONTINUATION	$42,408
2017	2017	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	4/17/2017	NON-COMPETING CONTINUATION	$381,658
														Subtotal = $424,066

Issue Date FY: 2016 ( Subtotal = $424,066 )
2016	2016	MICHIGAN STATE UNIVERSITY	301 ADMINISTRATION BLDG	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	7/14/2016	SUPPLEMENT FOR EXPANSION	$63,054
2016	2016	MICHIGAN STATE UNIVERSITY	301 ADMINISTRATION BLDG	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/2/2016	NON-COMPETING CONTINUATION	$361,012
														Subtotal = $424,066

Issue Date FY: 2015 ( Subtotal = $374,387 )
2015	2015	MICHIGAN STATE UNIVERSITY	301 ADMINISTRATION BLDG	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/3/2015	NEW	$374,387
														Subtotal = $374,387

Grand Total All Awards = $4,748,676

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Regulation of enteric motor neurocircuits by enteric glia in health and disease

Award Number: R01DK103723

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: 07/15/2015

PERIOD OF PERFORMANCE END DATE: 04/30/2030

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