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Regulation of Viscerosensory Sympathetic Reflexes: The Role of Diet-Derived Lipid Mediators.

Award Number: R01DK121812
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Gastrointestinal and cardiovascular health are intimately linked, yet the mechanism by which diet-derived lipid metabolites and the gut microbial flora impact efferent sympathetic nerve activity is largely unknown. Work from our laboratory and others’ provides increasing evidence that the enteric nervous system directly influences the sympathetic control of systemic blood pressure. The viscerosensory-sympathetic network is a functional neural circuit connecting afferent sensory fibers of the gut and efferent vasoconstrictor neurons at the level of the spinal cord. While this neural circuitry likely influences systemic blood pressure in able-bodied individuals, its role in the development of severe hypertensive crises in patients living with spinal cord injury (SCI) is irrefutable. Autonomic dysreflexia (AD) is often a clinical emergency in SCI individuals and is characterized by paroxysmal hypertension in response to otherwise innocuous visceral stimuli (e.g. fecal impaction). Despite its obvious significance, mechanisms involved in the regulation of viscerosensory-sympathetic reflexes (VSSRs) are poorly understood. Our preliminary studies indicate that C-fiber sensory neurons expressing transient receptor potential cation channel V1 (TRPV1) are involved in the afferent limb of the viscerosensory-sympathetic circuitry. Our proposal seeks to (Aim 1) provide a mechanistic understanding of the role of diet-derived lipid mediators in exaggerating the AD phenotype, (Aim 2) interrogate novel therapeutic strategies for attenuating sympathetic hyperreflexia following SCI, and (Aim 3) define the role of SCI-associated gut dysbiosis in contributing to the production of pathogenic diet-derived lipid mediators. Our central hypotheses identify new pathogenic factors (dietary fatty-acid content and SCI-associated dysbiosis) and a biochemical mechanism (diet-derived TRPV1 lipid ligands) that may be independent targets for therapeutic intervention. Uniquely, our rationally designed therapeutic strategies target the major underlying cause of AD (i.e. visceral C-fiber hypersensitivity) rather than the symptomatic outcome (i.e. acute hypertensive crisis) and thus constitute a major paradigm shift.


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: 2023 ( Subtotal = $460,691 )
2023	2023	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/10/2023	NON-COMPETING CONTINUATION	$460,691
														Subtotal = $460,691

Issue Date FY: 2022 ( Subtotal = $460,691 )
2022	2022	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/28/2022	NON-COMPETING CONTINUATION	$460,691
														Subtotal = $460,691

Issue Date FY: 2021 ( Subtotal = $464,984 )
2021	2021	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/26/2021	NON-COMPETING CONTINUATION	$464,984
														Subtotal = $464,984

Issue Date FY: 2020 ( Subtotal = $442,881 )
2020	2020	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/17/2020	NEW	$442,881
														Subtotal = $442,881

Grand Total All Awards = $1,829,247

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Regulation of Viscerosensory Sympathetic Reflexes: The Role of Diet-Derived Lipid Mediators.

Award Number: R01DK121812

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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