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Structural, Molecular and Functional Specialization in Osteocyte Mechanosensing

Award Number: R01AR070547
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/11/2018
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Structural, Molecular and Functional Specialization in Osteocyte Mechanosensing - ABSTRACT Bone adapts its structure to mechanical loading. This adaption is essential for growing the right skeleton and maintaining its integrity throughout life. Osteocytes are the cells responsible for sensing and coordinating response to mechanical load. Key recent discoveries reported by our group during the last several years established that osteocyte cell processes function as unique mechanosensory elements. Processes are >10-fold more sensitive to mechanical stimuli than osteocyte cell bodies. Moreover, this triggering of Ca2+ signaling from cell processes occurs through a unique complex of aVb3 integrins, membrane channels and receptors, that occur at attachment points to the canalicular walls, and which we call the “Osteocyte mechanosome.” This proposal is based on the global hypothesis that a novel structure localized on osteocyte processes, the osteocyte mechanosome, detects and transduces mechanical signals. To date, we have identified four key osteocyte mechanosome components: αVβ3 integrin, pannexin1, P2X7 receptor (P2X7R) and the CaV3.2 T-type calcium channel. Our multidisciplinary team will test this hypothesis by multiple approaches in each of three aims. In Aim 1 we will combine biochemical techniques (co-immunoprecipitation, surface plasmon resonance) and imaging modalities (FRAP, FRET and STORM super-resolution microscopy) to define comprehensively the structural and dynamic properties of this heretofore unknown transduction complex, the osteocyte mechanosome in osteocytic cells in vitro. In Aim 2 we test how pharmacological and genetic alteration of individual mechanosome components alters upstream (Ca2+) and downstream (to bone) signaling in osteocytic cells in vitro. In Aim 3, we will combine our novel OtGP3 osteocyte Ca2+ reporter mice-in vivo loading/imaging system with pharmacological manipulations to confirm effects of key mechanosome components (as identified in Aims 1 and 2) on osteocyte Ca2+ response and on downstream signaling. We will also use this approach to answer the fundamental question of whether osteocyte Ca2+ responses to mechanical loading altered by loss of constitutive sex hormones (estrogen/androgen) or by anabolic PTH.


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 = $0 )
2025	2022	RESEARCH FOUNDATION OF THE CITY UNIVERSITY OF NEW YORK	160 CONVENT AVE	NEW YORK	NY	10031	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	4/18/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	RESEARCH FOUNDATION OF THE CITY UNIVERSITY OF NEW YORK	160 CONVENT AVE	NEW YORK	NY	10031	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	3/20/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $628,236 )
2022	2022	RESEARCH FOUNDATION OF THE CITY UNIVERSITY OF NEW YORK	160 CONVENT AVE	NEW YORK	NY	10031	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	4/21/2022	NON-COMPETING CONTINUATION	$628,236
														Subtotal = $628,236

Issue Date FY: 2021 ( Subtotal = $615,547 )
2021	2021	RESEARCH FOUNDATION OF THE CITY UNIVERSITY OF NEW YORK	160 CONVENT AVE	NEW YORK	NY	10031	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	4/15/2021	NON-COMPETING CONTINUATION	$615,547
														Subtotal = $615,547

Issue Date FY: 2020 ( Subtotal = $634,586 )
2020	2020	RESEARCH FOUNDATION OF THE CITY UNIVERSITY OF NEW YORK	160 CONVENT AVE	NEW YORK	NY	10031	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	4/6/2020	NON-COMPETING CONTINUATION	$634,586
														Subtotal = $634,586

Issue Date FY: 2019 ( Subtotal = $634,586 )
2019	2019	RESEARCH FOUNDATION OF THE CITY UNIVERSITY OF NEW YORK	160 CONVENT AVE	NEW YORK	NY	10031	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	4/24/2019	NON-COMPETING CONTINUATION	$634,586
														Subtotal = $634,586

Issue Date FY: 2018 ( Subtotal = $648,836 )
2018	2018	RESEARCH FOUNDATION OF THE CITY UNIVERSITY OF NEW YORK	160 CONVENT AVE	NEW YORK	NY	10031	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	7/11/2018	NEW	$648,836
														Subtotal = $648,836

Grand Total All Awards = $3,161,791

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Structural, Molecular and Functional Specialization in Osteocyte Mechanosensing

Award Number: R01AR070547

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/11/2018

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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