Tuesday, July 1, 2025 7/1/2025

Mechanisms and Treatment of Hajdu Cheney Syndrome

Award Number: R01AR078149
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: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2026

Group Awards By:

View Award Description

Mechanisms and Treatment of Hajdu Cheney Syndrome - PROJECT SUMMARY/ABSTRACT Notch receptors play a critical role in cell fate decisions and in the regulation of bone remodeling, either directly or through the induction of their target genes, namely Hairy Enhancer of Split (Hes) and Hes-related with YRPW motif (Hey). Hajdu Cheney Syndrome (HCS) is a devastating disease characterized by developmental abnormalities, acroosteolysis and bone loss with fractures. HCS is associated with mutations in exon 34 of NOTCH2 upstream of the PEST domain leading to NOTCH2 stabilization and gain-of-function. We created a mouse model of HCS (Notch2tm1.1Ecan) that presents with osteopenia due to enhanced osteoclastogenesis and bone resorption. These events are secondary to an increase in receptor activator of nuclear factor Kappa B ligand (RANKL) by cells of the osteoblast lineage, and to direct effects of NOTCH2 in cells of the myeloid lineage. In this lineage, the expression of HES1 is induced by NOTCH2 and the inactivation of Hes1 in the osteoclast lineage reverses the in vitro and in vivo phenotype of HCS mutants. Moreover, HES1 induces osteoclastogenesis directly and as a result causes osteopenia in vivo. This reveals a previously unrecognized function of HES1 in osteoclast differentiation and function that will be explored as part of the proposed research. An additional goal of the proposed work is to develop ways to correct the skeletal manifestations of HCS by targeting the mutation with Notch2 antisense oligonucleotides (ASO), a strategy that would be applicable to other genetic disorders of the skeleton. Our specific aims are: Aim 1) To determine the role of HES1 in osteoclastogenesis. Our goals are to induce and inactivate Hes1 specifically in cells of the osteoclast lineage to determine its contribution to osteoclast differentiation and bone remodeling as determined by microcomputed tomography and histomorphometry; Aim 2) To establish that the Notch2tm1.1Ecan mutation can be targeted. We will determine whether the Notch2tm1.1Ecan mutation can be downregulated specifically and the Notch2tm1.1Ecan skeletal phenotype ameliorated by the administration of antisense oligonucleotides targeting the Notch26955C>T mutation; and Aim 3) To validate the mechanisms of the HCS phenotype and ASO approach in NOTCH2 mutant-induced pluripotent (iPS) cells. To this end, we created NOTCH2HCS mutant iPS cell lines to study the impact of the mutation on osteoclastogenesis and the efficacy of ASOs in downregulating NOTCH2 mutant alleles. The goals of the proposed work are to understand the mechanisms and develop specific antisense technology to treat the skeletal manifestations of a devastating NOTCH2-associated disease.


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 = $349,976 )
2025	2025	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	4/18/2025	NON-COMPETING CONTINUATION	$324,720
2025	2025	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	5/6/2025	NON-COMPETING CONTINUATION	$25,256
														Subtotal = $349,976

Issue Date FY: 2024 ( Subtotal = $349,976 )
2024	2024	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	8/2/2024	NON-COMPETING CONTINUATION	$25,256
2024	2024	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	4/18/2024	NON-COMPETING CONTINUATION	$324,720
														Subtotal = $349,976

Issue Date FY: 2023 ( Subtotal = $360,800 )
2023	2023	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	5/25/2023	NON-COMPETING CONTINUATION	$360,800
														Subtotal = $360,800

Issue Date FY: 2022 ( Subtotal = $357,192 )
2022	2022	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	6/29/2022	NON-COMPETING CONTINUATION	$357,192
														Subtotal = $357,192

Issue Date FY: 2021 ( Subtotal = $360,800 )
2021	2021	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	8/16/2021	NEW	$0
2021	2021	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	6/24/2021	NEW	$360,800
														Subtotal = $360,800

Grand Total All Awards = $1,778,744

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Mechanisms and Treatment of Hajdu Cheney Syndrome

Award Number: R01AR078149

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: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2026

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer