Thursday, July 3, 2025 7/3/2025

The Role of TRAPPC9 in Osteoclast Differentiation and Function

Award Number: R01AR077762
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: 08/01/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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The Role of TRAPPC9 in Osteoclast Differentiation and Function - Intellectual disability (ID) results from developmental conditions that are characterized by significant deficits in intellectual functioning with a prevalence of 1-3% in general population. In most cases, patients with ID also present with skeletal abnormalities. Recent studies identified several different nonsense mutations in the trafficking protein particle complex (TRAPPC9) gene in both consanguineous and non-consanguineous families. Patients with TRAPPC9 mutations share phenotypic features including unique facial appearance, skeletal abnormalities, moderate-to-severe ID, highlighting the importance of TRAPPC9 in both brain and skeletal development. However, its precise role in normal skeletogenesis remains obscure. TRAPPC9 is known as NIBP [NFkB inducing kinase (NIK) and IkB kinase 2 (IKK2) binding protein]. It enhances cytokine- induced NFkB activation by increasing the kinase activities of IKK2 and NIK, modulating both the canonical and non-canonical NFkB signaling. In addition, TRAPPC9 is also critical to intracellular vesicular trafficking. The relative importance of NFkB signaling and vesicular trafficking to the skeletal phenotype in TRAPPC9 patients is unknown. In this application, we propose to study the role of TRAPPC9 in normal bone physiology and its role in osteoclast (OC) differentiation and function. Our preliminary studies show that TRAPPC9 is expressed in bone cells and binds NIK and IKK2 in OC in vitro. Functional knockdown of TRAPPC9 in OC leads to defective OC differentiation and function. In addition, floxed-TRAPPC9 transgenic mice crossed with myeloid-specific Cre (LysM) mice, develop osteopetrosis. Together these results strongly suggest TRAPPC9 is a positive regulator of osteoclastogenesis. TRAPPC9 also mediates vesicular trafficking. Here we present data that TRAPPC9 binds to L-plastin and regulates actin-ring formation and OC function. These findings and others presented in this application, prompted us to hypothesize that TRAPPC9 regulates osteoclast differentiation and function via modulation of NFkB-dependent and unrelated signaling pathways. To test our hypothesis, we propose to examine the functional role of TRAPPC9 using conditional null mice in OC lineage. In addition, we will determine the mechanisms by which TRAPPC9 modulates NFkB-dependent signaling in OC. Aim 1 will focus on characterization of the skeletal phenotype of TRAPPC9 conditional knockout mice and will examine the impact of TRAPPC9 deficiency on OC differentiation and function. Aim 2 will elucidate the molecular mechanism by which TRAPPC9 regulates of NFkB signaling and determine the physiological role of TRAPPC9 in osteoporosis. Aim 3 will examine the role of TRAPPC9 in OC polarization and function. In sum, these experiments will decipher the role of TRAPPC9 in regulating bone mass and the mechanisms by which TRAPPC9 regulates NFkB signaling. The successful accomplishment of this project will generate new clues to enhance our knowledge of NFkB signaling in bone cells and the development of therapeutic modalities for bone loss diseases.


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 = $338,049 )
2025	2025	NORTHEAST OHIO MEDICAL UNIVERSITY	4209 STATE ROUTE 44	ROOTSTOWN	OH	44272	PORTAGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	3/5/2025	NON-COMPETING CONTINUATION	$338,049
														Subtotal = $338,049

Issue Date FY: 2024 ( Subtotal = $367,335 )
2024	2024	NORTHEAST OHIO MEDICAL UNIVERSITY	4209 STATE ROUTE 44	ROOTSTOWN	OH	44272	PORTAGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	5/31/2024	NON-COMPETING CONTINUATION	$26,509
2024	2024	NORTHEAST OHIO MEDICAL UNIVERSITY	4209 STATE ROUTE 44	ROOTSTOWN	OH	44272	PORTAGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	1/26/2024	NON-COMPETING CONTINUATION	$340,826
														Subtotal = $367,335

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	NORTHEAST OHIO MEDICAL UNIVERSITY	4209 STATE ROUTE 44	ROOTSTOWN	OH	44272	PORTAGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	8/31/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $341,377 )
2022	2022	NORTHEAST OHIO MEDICAL UNIVERSITY	4209 SR 44	ROOTSTOWN	OH	44272	PORTAGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	7/27/2022	NON-COMPETING CONTINUATION	$341,377
														Subtotal = $341,377

Issue Date FY: 2021 ( Subtotal = $337,764 )
2021	2021	NORTHEAST OHIO MEDICAL UNIVERSITY	4209 SR 44	ROOTSTOWN	OH	44272	PORTAGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	8/3/2021	NON-COMPETING CONTINUATION	$337,764
														Subtotal = $337,764

Issue Date FY: 2020 ( Subtotal = $365,035 )
2020	2020	NORTHEAST OHIO MEDICAL UNIVERSITY	4209 SR 44	ROOTSTOWN	OH	44272	PORTAGE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	7/28/2020	NEW	$365,035
														Subtotal = $365,035

Grand Total All Awards = $1,749,560

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The Role of TRAPPC9 in Osteoclast Differentiation and Function

Award Number: R01AR077762

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: 08/01/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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