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Molecular Etiology of Spondyloepimetaphyseal Dysplasia with Joint Laxity - Leptodactylic Type

Award Number: F31AR074887
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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PROJECT SUMMARY Skeletal dysplasias are disorders of skeletal development and occur at a rate of approximately 1 in 5000 births. DNA sequencing is capable of identifying causative genes for these disorders, but mechanistic studies are needed to understand how identified mutations cause abnormal bone growth. This proposal addresses the mechanistic gap in knowledge for spondyloepimetaphyseal dysplasia with joint laxity- leptodactylic type (SEMDJL2), a skeletal dysplasia characterized by defects in endochondral bone formation. Causative dominant mutations in the gene KIF22 have been identified in SEMDJL2 patients. However, the function of KIF22, a kinesin motor protein, in bone development and the consequences of single amino acid changes in KIF22 on this process are not known. Endochondral bone growth requires the differentiation of mesenchymal stem cells to chondrocytes and osteoblasts. Chondrocytes proliferate and produce a calcified cartilage template for bone growth. Upon chondrocyte hypertrophy, osteoblasts are recruited to the calcified cartilage and deposit bone matrix. We hypothesize that mutations in KIF22 result in disruption of this process via defects in cell division and proliferation, defects in the differentiation of progenitors to chondroctyes and osteoblasts, or defects in both division and differentiation. To test the function of KIF22 in division and proliferation of progenitor cells at the cellular level, we will use a combination of fixed and live cell imaging to assess the ability of KIF22 with SEMDJL2- derived mutations to generate forces for the movement of chromosome arms in mitotic cells. Consequent cell cycle arrest or reduction in proliferation will be assessed. To determine whether mutations in KIF22 result in SEMDJL2 pathology due to defects in pluripotent mesenchymal stem cell differentiation, we will induce differentiation of cells to chondrocytes and osteoblasts in vitro. Differentiation and maturation will be assessed in these systems by histological staining for matrix production and mineralization, as well as expression levels of markers indicative of chondrocytes, osteoblasts, or osteocytes. Together, these assays will allow us to determine the mechanism by which mutations in KIF22 affect endochondral bone growth by combining expertise in cell division with expertise in the control of bone development.


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: 2023 ( Subtotal = -$7,232 )
2023	2021	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	5/15/2023	NON-COMPETING CONTINUATION	-$7,232
														Subtotal = -$7,232

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	3	10/26/2021	NON-COMPETING CONTINUATION	$0
2022	2020	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	10/26/2021	NON-COMPETING CONTINUATION	$0
2022	2019	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	10/21/2021	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $34,070 )
2021	2021	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	5/13/2021	NON-COMPETING CONTINUATION	$34,070
														Subtotal = $34,070

Issue Date FY: 2020 ( Subtotal = $33,398 )
2020	2020	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	5/18/2020	NON-COMPETING CONTINUATION	$29,520
2020	2020	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	7/1/2020	NON-COMPETING CONTINUATION	$3,878
														Subtotal = $33,398

Issue Date FY: 2019 ( Subtotal = $32,745 )
2019	2019	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	7/1/2019	NEW	$0
2019	2019	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	7/1/2019	NEW	$32,745
														Subtotal = $32,745

Grand Total All Awards = $92,981

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Molecular Etiology of Spondyloepimetaphyseal Dysplasia with Joint Laxity - Leptodactylic Type

Award Number: F31AR074887

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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