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Neuro-immune interactions at the intestinal surface

Award Number: R01DK126407
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: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Neuro-immune interactions at the intestinal surface - The gastrointestinal (GI) tract is the largest environmental interface of the mammalian body, which faces the challenge of maintaining tolerance to dietary and microbial antigens while protecting against pathogen invasion. In addition to hosting a large collection of immune cells, the GI tract contains diverse and numerous populations of glial cells and neurons, both intrinsic and extrinsic. Enteric neurons are responsible for controlling various physiological functions but can be targeted during enteric infections, resulting in functional gastrointestinal disorders after pathogen clearance. While some mechanisms underlying neuronal damage have been uncovered, the host and microbial factors that trigger enteric neuron loss and regeneration remain unclear. Over the past three years, we have uncovered new mechanisms of enteric neuronal cell death following infection or microbiota depletion and described the role of the gut microbiota and intestinal immune cells in regulating enteric neuron maintenance and function. In new preliminary data presented in the application, we provide evidence that enteric glial cells (EGC) experience a similar loss as enteric neurons following infection and antibiotic treatment. Additionally, our new data strongly suggest that EGC de-differentiation may play a role in neuronal recovery observed after microbiota transplantation. Finally, candidate metabolites involved in dysbiosis- associated neuronal death and neuronal recovery were identified. Based on these observations, we hypothesize that dysbiosis triggered by infection or antibiotic treatment generates ligands that trigger inflammasome- associated neuronal loss. Upon injury, glia-to-neuron dedifferentiation mediates neuronal recovery in a microbiota-dependent manner. The three complementary aims will delve deeper into these observations to reveal novel cellular and molecular mechanisms of microbiota-dependent neuronal death and regeneration, using novel imaging, state-of-the-art single-nuclei transcriptomics and chromatic accessibility, metabolomics, murine genetic fate-mapping, gain- and loss-of-function, and gnotobiotic approaches. In Aim 1, we will define the bacterial species and metabolites associated with specific glia and neuronal cell death after infection or antibiotic treatment. In Aim 2, we will assess the cellular dynamics of EGC and neuronal recovery after microbiota transplantation, followed by fate-mapping studies to define the possible role of glial cell de-differentiation in this process. Finally, Aim 3 will use complementary gnotobiotic and metabolomic approaches to identify bacterial signals and host pathways that induce gliogenesis and neurogenesis in different contexts. Overall, this proposal seeks to uncover novel mechanisms of microbiota-dependent neuronal death and regeneration with implications for the treatment of functional gastrointestinal disorders.


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 = $611,547 )
2025	2025	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	5/19/2025	NON-COMPETING CONTINUATION	$611,547
2025	2023	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/12/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $611,547

Issue Date FY: 2024 ( Subtotal = $628,922 )
2024	2024	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	2/22/2024	COMPETING CONTINUATION	$628,922
														Subtotal = $628,922

Issue Date FY: 2023 ( Subtotal = $519,541 )
2023	2023	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/10/2023	NON-COMPETING CONTINUATION	$519,541
														Subtotal = $519,541

Issue Date FY: 2022 ( Subtotal = $519,541 )
2022	2022	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/28/2022	NON-COMPETING CONTINUATION	$519,541
														Subtotal = $519,541

Issue Date FY: 2021 ( Subtotal = $519,541 )
2021	2021	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/25/2021	NON-COMPETING CONTINUATION	$519,541
														Subtotal = $519,541

Issue Date FY: 2020 ( Subtotal = $519,541 )
2020	2020	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/26/2020	NEW	$519,541
														Subtotal = $519,541

Grand Total All Awards = $3,318,633

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Neuro-immune interactions at the intestinal surface

Award Number: R01DK126407

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: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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