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Role of sensory nerves in perivascular inflammation and vasomotor dysfunction with inflammatory bowel disease

Award Number: R01HL157038
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary and Abstract Inflammatory Bowel Disease (IBD) is an increasingly prevalent chronic disease marked by aberrant immune responses and intestinal and extra-intestinal inflammation. IBD is comorbid with cardiovascular disease and associated with decreased blood flow to the intestines, with a critical but poorly-studied role for the mesenteric (MAs) arteries that regulate intestinal perfusion. Perivascular sensory nerves (PSNs) continuously innervate the MA adventitia and perivascular adipose tissue (PVAT), regulating vasomotor function and facilitating blood flow by dilating MAs and inhibiting sympathetic vasoconstriction. With IBD, these PSN functions are severely impaired, and the PVAT that is normally anticontractile becomes procontractile through an unknown mechanism, further impairing MA dilation. The sensory neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP) may also be important in these IBD-related vascular dysfunctions, as they are linked to disease severity and can mediate perivascular neuro-immune and neuro-adipose signaling through activation of local immune cells. Previous work demonstrates that macrophages accumulate in both the MA adventitia and PVAT during IBD, and macrophage depletion restores the ability of PSNs to dilate MAs and inhibit sympathetic constriction. This suggests that perivascular macrophages can modulate arterial function with IBD, likely through a mechanism involving sensory neurotransmitters in the adventitia and PVAT. What remains unclear is how macrophages participate in PSN, PVAT, and blood flow dysfunction and when these changes occur in IBD development. This project will test the overall hypothesis that PSN neurotransmitter released in adventitia and PVAT of MAs promotes macrophage activation, accumulation, and inflammatory mediator release, leading to vasomotor defects and impaired blood flow early in IBD pathogenesis. To investigate these relationships, the immune-driven, Helicobacter hepaticus-induced IL10-/- mouse model of IBD will be used to address 3 research Aims. Aim 1 will use confocal imaging, flow cytometry, and in vivo blood flow measurements at timepoints throughout IBD development to determine when macrophage infiltration causes PSN and PVAT dysfunction and impairs blood flow compared to the development of colon inflammation. Aim 2 will use sensory denervation and transgenic mice lacking PVAT in conjunction with isolated artery preparations to determine whether the presence and activity of PSNs and/or PVAT drive macrophage infiltration around MAs with IBD. Aim 3 will use advanced imaging, primary adventitial and PVAT macrophages, and biochemical assays to test whether sensory neuropeptides can activate macrophages from the MA adventitia and PVAT to release inflammatory mediators. This project will uniquely define the role of PSNs and their signaling pathways in neuro-immune-adipose interactions mediating vasomotor function, and it will determine how these pathways are affected during the pathogenesis of IBD. Results will provide new insight towards developing selective therapeutic strategies for treating vascular dysfunction and impaired intestinal blood flow to improve quality of life for IBD patients.


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 = $377,125 )
2024	2024	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	000	4	3/1/2024	NON-COMPETING CONTINUATION	$377,125
														Subtotal = $377,125

Issue Date FY: 2023 ( Subtotal = $377,125 )
2023	2023	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	000	3	3/14/2023	NON-COMPETING CONTINUATION	$377,125
														Subtotal = $377,125

Issue Date FY: 2022 ( Subtotal = $377,125 )
2022	2022	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	001	2	5/31/2022	NON-COMPETING CONTINUATION	$37,712
2022	2022	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	000	2	3/7/2022	NON-COMPETING CONTINUATION	$339,413
														Subtotal = $377,125

Issue Date FY: 2021 ( Subtotal = $376,282 )
2021	2021	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	000	1	3/15/2021	NEW	$338,653
2021	2021	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	001	1	7/30/2021	NEW	$37,629
														Subtotal = $376,282

Grand Total All Awards = $1,507,657

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Role of sensory nerves in perivascular inflammation and vasomotor dysfunction with inflammatory bowel disease

Award Number: R01HL157038

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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