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Osteogenesis imperfecta caused by TMEM38B mutation: a deep investigation of cellular and extracellular consequences to identify new therapeutic targets

Award Number: R03AR084261
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: 09/25/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Osteogenesis imperfecta caused by TMEM38B mutation: a deep investigation of cellular and extracellular consequences to identify new therapeutic targets - Project Summary There is no cure for osteogenesis imperfecta (OI or brittle bone disease), a group of heritable genetic disorders affecting 1:15,000 births. The most evident clinical hallmarks of OI are bone fragility and skeletal deformities. Mutations in trimeric intracellular cation channel B (TRIC-B), an endoplasmic reticulum potassium (K+) channel encoded by transmembrane protein 38 B (TMEM38B) gene and modulating Calcium (Ca2+) flux, cause the rare recessive form of the disease, namely OI type XIV. How a potassium channel is responsible for a heritable bone disease is puzzling the field. Calcium is indispensable for several cell activities including signal transduction pathways that regulate osteoblast differentiation and function. We here plan to identify the intra and extra-cellular mechanisms responsible for the skeletal defects and fragility caused by loss-of-function mutations in TRIC-B, with the goal to unveil a druggable target for OI therapy. We recently proved that the Calcium flux impairment due to osteoblast TRIC-B loss-of-function compromises the TGF-β/SMAD signaling. Based on preliminary data, we hypothesize that TMEM38B mutation generates an impairment of β-catenin/WNT pathway and of cell adhesion, which results in an increased bone fragility by compromising bone matrix structure and composition, thus reducing strength and toughness. Specific aims are to: 1) dissect TRIC-B role in osteoblast intracellular signaling affecting activity and adhesion; 2) determine the mechanism by which osteoblast specific absence of TRIC-B develops bone fragility. To address TRIC-B bone function, we generated an osteoblast specific TRIC-B knock-out mouse that reproduces patients’ skeletal outcome. The consequence of loss of TRIC-B on osteoblast WNT pathways and cell adhesion will be investigated by advanced molecular, biochemical and high-resolution imaging techniques (AIM 1). Bone strength and fracture toughness combined with second harmonic generation microscopy and spectroscopic analysis of the bone tissue collagen fiber structure and composition, respectively, will inform on the mechanism through which depletion of Tmem38b generates bone fragility (AIM 2). This work will shed light on TRIC-B role in osteoblasts and extracellular matrix to identify a druggable target for OI.


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	2024	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	8/12/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $159,594 )
2024	2024	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	001	1	9/26/2024	NEW	$0
2024	2024	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	9/25/2024	NEW	$159,594
														Subtotal = $159,594

Grand Total All Awards = $159,594

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Osteogenesis imperfecta caused by TMEM38B mutation: a deep investigation of cellular and extracellular consequences to identify new therapeutic targets

Award Number: R03AR084261

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: 09/25/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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