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Molecular mediators of muscle spindle mechanosensation

Award Number: R16GM153600
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: 03/18/2024
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Molecular mediators of muscle spindle mechanosensation - PROJECT SUMMARY: Molecular mediators of muscle spindle mechanosensation. Many conditions, including aging, chemotherapy-induced peripheral neuropathy, and neuromuscular diseases, negatively impact the function of muscle proprioceptors. The Group Ia and II muscle spindle afferents are slowly-adapting mechanoreceptors and provide the primary sensory information for proprioception and comprise the sensory arm of the muscle stretch reflex. The exact molecular mechanism used to translate muscle stretch into action potentials in these neurons is only incompletely understood. However, the mechanically gated ion channel PIEZO2 is known to be necessary for normal stretch sensitivity and multiple genetic diseases that increase or decrease PIEZO2 channel function are known to impair proprioception and motor behaviors. The voltage gated sodium channel NaV1.1 and vesicle-released glutamate are also known to be necessary for maintained excitability during static stretch. The overarching goal of this proposal is to understand how the developmental timing of dysfunction in those proteins alters muscle spindle afferent mechanosensation. We will determine how a mouse model with a gain of function mutation to Piezo2 which leads to Distal Arthrogryposis Type 5 alters mechanosensation in the muscle spindle afferents when it is expressed throughout development or only after the muscle spindle is developed (Aim 1). Similarly, we will determine whether loss of Piezo2 once the muscle spindle develops eliminates stretch sensitive firing as it does following constitutive loss. We will also use a model of Angelman Syndrome that decreases Piezo2 channel activity to determine how mechanosensation is impaired under a less complete decrease in Piezo2 function (Aim 2). Finally, we will determine whether loss of NaV1.1 after the muscle spindle has developed leads to similar inconsistent static phase firing as observed following constitutive loss and whether NaV1.1 and/or vesicle-released glutamate are less important for mediating the more rapidly-adapting stretch responses seen before the muscle spindle matures (Aim 3). These results will increase understanding of how alteration in the function of key components of the muscle spindle afferent mechanotransduction machinery affect function during genetic disorders or other later-onset disease states that target these molecular mediators.


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 = $131,850 )
2025	2025	SAN JOSE STATE UNIVERSITY RESEARCH FOUNDATION	210 N 4TH ST FL 4	SAN JOSE	CA	95112	SANTA CLARA	USA	Biomedical Research and Research Training	000	2	2/24/2025	NON-COMPETING CONTINUATION	$131,850
														Subtotal = $131,850

Issue Date FY: 2024 ( Subtotal = $146,500 )
2024	2024	SAN JOSE STATE UNIVERSITY RESEARCH FOUNDATION	210 N 4TH ST FL 4	SAN JOSE	CA	95112	SANTA CLARA	USA	Biomedical Research and Research Training	000	1	3/18/2024	NEW	$146,500
														Subtotal = $146,500

Grand Total All Awards = $278,350

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Molecular mediators of muscle spindle mechanosensation

Award Number: R16GM153600

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: 03/18/2024

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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