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Modulation of interoception by TRPV1-expressing renal afferent nerves

Award Number: R01DK147762
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: 05/15/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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Modulation of interoception by TRPV1-expressing renal afferent nerves - The afferent innervation of the kidney remains poorly understood. Gaps in knowledge persist regarding the precise location of afferent renal nerves (ARN) in the kidney, their origin in spinal and vagal sensory ganglia, their interaction with central nervous system (CNS) interoceptive circuits, and their functional properties under physiological and pathophysiological conditions. Clinical trials for catheter-based renal denervation for drug resistant hypertension (HTN) have shown additional benefits independent of reducing blood pressure. These benefits can only be explained by ARN ablation. Findings from our preliminary data and the literature suggest that input to the CNS from TRPV1-expressing kidney-innervating primary afferent neurons (TRPV1+ kiPAN) are involved in the central regulation of blood pressure. The objective of this proposal is to define the diversity of ARN that express the capsaicin receptor TRPV1 and the impact of their CNS input on central interoceptive networks. Our central hypothesis is that input from distinct subtypes of TRPV1+ kiPAN can modulate CNS interoceptive circuits. This proposal will address this hypothesis in two aims. In Aim 1, we will define the modulation of central interoceptive circuits by TRPV1+ ARN under normal conditions and during neurogenic HTN. We hypothesize that increased activity of TRPV1+ ARN is reflected in altered neuronal activity in central interoceptive circuits under normal and HTN conditions. We will use the TRAP2 transgenic mouse line to conduct global analysis of CNS neuronal activation after capsaicin stimulation of ARN to identify CNS regions that process TRPV1+ ARN input. We will use fluorescent in situ hybridization (FISH) to determine the neurochemical subtype of these activated neurons and employ viral vector tracing to define the projections of brainstem and spinal neurons that receive direct input from TRPV1+ ARN. In Aim 2, we will determine if subtypes of TRPV1+ kiPAN have distinct contributions to renal interoception. We will use single-cell RNA sequencing, FISH, and neurotracing to test the hypothesis that distinct TRPV1+ kiPAN subtypes innervate the renal cortex and pelvis, and that these subtypes undergo specific transcriptional changes during neurogenic HTN. We will test if TRPV1+ kiPAN are spontaneously active and if their activity increases during neurogenic HTN using in vivo imaging of identified TRPV1+ kiPAN, and use FISH to identify the transcriptional subtypes. We will visualize the peripheral processes of TRPV1+ kiPAN within the renal pelvis and cortex using retrograde viral vector tracing to test if the kidney is innervated by spinal and vagal primary afferent neurons with different peripheral termination patterns. There is a critical need for thorough analysis of the interoceptive functions of ARN in order to harness the therapeutic potential of their manipulation through pharmacological or non-invasive neuromodulation approaches. The proposed work will transform our understanding of the diversity of kiPAN and the integration of their inputs in central interoceptive circuits. We expect that these studies will provide insights into central and peripheral neuroplasticity during neurogenic hypertension, which may inform future therapeutic development.


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 = $694,934 )
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/15/2026	NEW	$694,934
														Subtotal = $694,934

Grand Total All Awards = $694,934

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Modulation of interoception by TRPV1-expressing renal afferent nerves

Award Number: R01DK147762

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: 05/15/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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