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Investigating the Contributions of Chondrocyte Spindle Biophysics and Tissue Microenvironment to Skeletal Dysplasia

Award Number: F31AR087752
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 06/01/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Investigating the Contributions of Chondrocyte Spindle Biophysics and Tissue Microenvironment to Skeletal Dysplasia - PROJECT SUMMARY Our understanding of how the cell division process varies across different tissues at the molecular level is extremely limited. Most mitotic proteins are ubiquitously expressed, but dysregulation of these highly coordinated component parts can still lead to dysfunction in a tissue-specific manner. One such example can be found in patients with spondyloepimetaphyseal dysplasia with joint laxity type 2 (SEMDJL2), who present with skeletal tissue-specific defects in development. SEMDJL2-causing point mutations have been identified in the ubiquitous mitotic chromokinesin KIF22. We have shown that SEMDJL2-associated mutations in KIF22 disrupt chromosome segregation in anaphase and result in reduced proliferation, abnormal daughter cell nuclear morphology, and cytokinesis failure. Interestingly, the mutations did not disrupt KIF22 motor function or localization, but rather the mechanisms that regulate KIF22 activity over the course of mitosis, leaving the motor hyperactivated. Persistent KIF22 motor activity during anaphase impairs the separation of chromosomes after alignment, which subsequently results in cytokinesis defects. However, it remains to be determined how these effects cause skeletal tissue-specific defects, since KIF22 is ubiquitously expressed. Spatial constraints in the skeletal growth plate may restrain spindle pole separation in anaphase and impair cytokinesis by preventing daughter cells from pulling away from one another during division. These impairments may be amplified by aberrant polar ejection forces to a point where the cell can no longer divide normally. We predict that the skeletal tissue-specific sensitivity to activating mutations in KIF22 is due to a combination of chondrocyte-specific characteristics that impact the force balance within mitotic spindles and the spatial constraints imposed by the skeletal growth plate. Investigating the molecular mechanisms by which mutations in KIF22 selectively disrupt growth of skeletal tissue in SEMDJL2 patients will additionally provide insight into the chondrocyte-specific functional roles of KIF22, the regulatory mechanisms governing the activity of KIF22 during mitosis, and the effects of tissue architecture on cell division.


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 = $35,202 )
2026	2026	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	5/26/2026	NEW	$35,202
2026	2026	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	6/24/2026	NEW	$0
														Subtotal = $35,202

Grand Total All Awards = $35,202

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Investigating the Contributions of Chondrocyte Spindle Biophysics and Tissue Microenvironment to Skeletal Dysplasia

Award Number: F31AR087752

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 06/01/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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