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Pathogenic Mechanisms of Craniometaphyseal Dysplasia

Award Number: R01DE025664
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Pathogenic Mechanisms of Craniometaphyseal Dysplasia - Project Summary/Abstract Investigating pathogenic mechanisms for rare Mendelian disorders is important not only to identify therapeutic strategies for lifelong debilitating diseases but also to understand fundamental biological mechanisms. In this renewal application, we propose mechanistic and translational studies for craniometaphyseal dysplasia (CMD), an understudied craniotubular bone disorder characterized by lifelong progressing hyperostosis of craniofacial bones and abnormal shape of long bones. Continued bone accrual in CMD can lead to excruciating headaches, blindness, deafness, and facial palsy. Severe cases can be life-threatening. CMD patients are treated with repetitive, costly and risky surgeries when corrections of facial deformity are needed or severe neurological symptoms occur. Mutations in the progressive ankylosis protein (ANKH) and connexin 43 (Cx43) have been identified as causes for autosomal dominant and recessive CMD, respectively. To study CMD, we have generated state-of-the-art research tools, which include mouse models carrying CMD mutations, isogenic human induced pluripotent stem cells (hiPSCs) with or without CMD mutations, and bone resorbing cells (osteoclasts) derived from these hiPSCs. In the past funding period, we have discovered the rapid degradation of mutant ANKH(Human)/ANK(Mouse) protein and studied negative effects of mutant ANKH/ANK on the cytoskeleton, which determinates cell shape, size, and polarity. We also identified differentially expressed proteins in CMD osteoclasts and preferential binding partners for mutant ANK protein. However, CMD pathogenesis is not fully understood and potential therapeutics have not been explored. Our long-term goal is to utilize our research findings for identifying potential therapeutic targets to reduce or prevent the lifelong bone deposition in craniofacial bones. In the next 5 years, we will use animal models and molecular and cellular methodologies that we have developed to focus on mechanistic investigations and prepare for future clinical studies. Based on our preliminary data and previous publications we propose three specific aims. We will study the impact of CMD-mutant ANK on cellular acidification of osteoclasts (Aim 1) and on the bi-directional regulation between the cytoskeleton and an energy metabolism regulator in CMD (Aim 2). These are likely novel dominant functions of mutant ANK leading to CMD. In Aim 3 we will identify biomarkers that can be used to monitor the disease progression in patients and mouse models. We will also evaluate shifts in biomarker expression in response to experimental treatment regimen in our model systems. We expect that the proposed studies will give deeper insight into pathogenic mechanisms of CMD, knowledge needed to discover candidate targets for therapeutics. Biomarkers that correspond to disease progression or treatment efficacy will be the basis for future clinical studies.


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: 2026 ( Subtotal = $498,194 )
2026	2026	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Oral Diseases and Disorders Research	000	10	7/16/2026	NON-COMPETING CONTINUATION	$498,194
														Subtotal = $498,194

Issue Date FY: 2025 ( Subtotal = $498,194 )
2025	2025	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Oral Diseases and Disorders Research	000	9	7/11/2025	NON-COMPETING CONTINUATION	$498,194
														Subtotal = $498,194

Issue Date FY: 2024 ( Subtotal = $503,497 )
2024	2024	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Oral Diseases and Disorders Research	000	8	6/13/2024	NON-COMPETING CONTINUATION	$503,497
														Subtotal = $503,497

Issue Date FY: 2023 ( Subtotal = $513,773 )
2023	2023	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Oral Diseases and Disorders Research	003	7	6/29/2023	NON-COMPETING CONTINUATION	$513,773
2023	2022	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Oral Diseases and Disorders Research	002	6	6/28/2023	COMPETING CONTINUATION	$0
2023	2022	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Oral Diseases and Disorders Research	001	6	3/3/2023	COMPETING CONTINUATION	$135,943
2023	2020	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Oral Diseases and Disorders Research	000	5	3/3/2023	NON-COMPETING CONTINUATION	-$135,943
														Subtotal = $513,773

Issue Date FY: 2022 ( Subtotal = $502,797 )
2022	2022	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Oral Diseases and Disorders Research	000	6	5/27/2022	COMPETING CONTINUATION	$502,797
														Subtotal = $502,797

Issue Date FY: 2020 ( Subtotal = $398,750 )
2020	2020	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Oral Diseases and Disorders Research	000	5	6/15/2020	NON-COMPETING CONTINUATION	$398,750
														Subtotal = $398,750

Issue Date FY: 2019 ( Subtotal = $398,750 )
2019	2019	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Oral Diseases and Disorders Research	000	4	6/22/2019	NON-COMPETING CONTINUATION	$398,750
														Subtotal = $398,750

Issue Date FY: 2018 ( Subtotal = $398,750 )
2018	2018	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Oral Diseases and Disorders Research	000	3	6/6/2018	NON-COMPETING CONTINUATION	$398,750
														Subtotal = $398,750

Issue Date FY: 2017 ( Subtotal = $398,750 )
2017	2017	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Oral Diseases and Disorders Research	000	2	7/6/2017	NON-COMPETING CONTINUATION	$398,750
														Subtotal = $398,750

Issue Date FY: 2016 ( Subtotal = $398,750 )
2016	2016	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON CENTER	FARMINGTON	CT	06030	CAPITOL	USA	Oral Diseases and Disorders Research	000	1	6/10/2016	NEW	$398,750
														Subtotal = $398,750

Grand Total All Awards = $4,510,205

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Pathogenic Mechanisms of Craniometaphyseal Dysplasia

Award Number: R01DE025664

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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