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The Impact of Disrupting Sensory Innervation on Tibial Bone Mass

Award Number: R16GM150784
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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The Impact of Disrupting Sensory Innervation on Tibial Bone Mass - PROJECT SUMMARY Tibia and fibula fractures account for 10% of annual osteoporotic fractures leading to significant morbidity with a 10% mortality rate within 12 months of fracture. Low bone mineral density can dramatically increase fracture risk resulting from a decrease in bone formation by the osteoblast, an increase in bone resorption by the osteoclast, or both. A greater understanding of factors regulating tibial bone mineral density will help prevent tibial fracture through identification of at-risk individuals and treatment of low tibial bone mineral density. Sensory nerves signal to and from bone. Both signaling directions are critical aspects of bone homeostasis and bone health. Sensory nerve communication with bone has been linked to an increase in bone mineral density through direct and indirect communication between sensory nerves and both osteoblast and osteoclasts while denervation is linked to reduced bone mass. However, it is unclear what impact long-term disruption of these signaling pathways has on bone health. The saphenous nerve is primarily a sensory nerve with no known motor function. Injury to the saphenous nerve results in pain, numbness, and denervation of the nerve itself. Preliminary studies have demonstrated that the saphenous nerve innervates the tibia in mice. Preliminary data has shown that transection of the saphenous nerve reduces tibial nerve fiber density by 45-60% in the proximal, lateral-most periosteum of the tibia. However, the impact of saphenous nerve injury on tibial bone mineral density is unknown. We hypothesize that saphenous nerve denervation will alter bone remodeling within the tibia resulting in reduced bone mass. In order to test this hypothesis, Aim 1 will characterize the impact of saphenous nerve transection on tibial bone mass and innervation. These data will determine whether denervation of the tibia will result in a decreased bone mineral density, microarchitecture, cell number, and turnover. It will also further identify regions of innervation loss within the tibia following saphenous nerve injury. In an effort to delineate the mechanism of sensory regulation of bone, Aim 2 will assess the relative contribution of sensory nerve fiber subtypes on tibial bone mass through chemical ablation of peptidergic and non-peptidergic sensory neurons using resiniferatoxin and IB4-Saporin, respectively. As CGRP has been demonstrated to promote bone anabolism, we hypothesize that selective ablation of peptidergic sensory fibers will result in bone loss whereas selective ablation of non-peptidergic sensory fibers will not alter bone remodeling or bone mass. These data will reveal the sensory nerve fiber subtype necessary for maintaining bone mineral density. The proposed studies will define the saphenous nerve as an important regulator of bone homeostasis in the tibia. A greater understanding of the impact of nerve injury on bone mass will aid in elucidating new risk factors predisposing individuals to tibial fracture.


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 = $177,500 )
2025	2025	UNIVERSITY OF NEW ENGLAND	11 HILLS BEACH RD	BIDDEFORD	ME	04005	YORK	USA	Biomedical Research and Research Training	000	3	7/16/2025	NON-COMPETING CONTINUATION	$177,500
														Subtotal = $177,500

Issue Date FY: 2024 ( Subtotal = $177,500 )
2024	2024	UNIVERSITY OF NEW ENGLAND	11 HILLS BEACH RD	BIDDEFORD	ME	04005	YORK	USA	Biomedical Research and Research Training	000	2	8/5/2024	NON-COMPETING CONTINUATION	$177,500
														Subtotal = $177,500

Issue Date FY: 2023 ( Subtotal = $177,500 )
2023	2023	UNIVERSITY OF NEW ENGLAND	11 HILLS BEACH RD	BIDDEFORD	ME	04005	YORK	USA	Biomedical Research and Research Training	000	1	7/28/2023	NEW	$177,500
														Subtotal = $177,500

Grand Total All Awards = $532,500

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The Impact of Disrupting Sensory Innervation on Tibial Bone Mass

Award Number: R16GM150784

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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