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Molecular control of chondrocyte hypertrophy: an evolutionary approach

Award Number: F32AR082273
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: 09/01/2023
PERIOD OF PERFORMANCE END DATE: 01/06/2025

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Molecular control of chondrocyte hypertrophy: an evolutionary approach - Project Summary In mammals, cartilage is predominantly an embryonic tissue: the vast majority of cartilage is replaced by bone during the processes of hypertrophy and ossification, with cartilage persisting in relatively few places within the adult skeleton (e.g. in joints, as articular cartilage). Articular cartilage is an aneural, avascular tissue with very limited capacity for spontaneous repair, hence the prevalence in humans of cartilage pathologies like osteoarthritis. In contrast, cartilaginous fishes (sharks, skates, and rays) have undergone an evolutionary loss of bone, instead possessing a skeleton that is composed entirely of pre-hypertrophic cartilage, and that remains cartilaginous throughout life. Understanding how cartilaginous fishes arrest skeletal development prior to chondrocyte hypertrophy will shed new light on transcriptional features that could be employed for in vitro engineering of stable chondrocytes for the treatment of human cartilage injuries. Stem cell-based approaches for the treatment of articular cartilage injuries are currently hindered by the relative instability of mammalian cartilage cells (chondrocytes) in vitro and upon implantation into an injury site. In this project, the molecular development of cartilage in the little skate (Leucoraja erinacea) will be studied to discover gene expression correlates of their permanent cartilaginous skeleton. This project will begin with the use of single-cell RNA-sequencing to identify genes that are differentially expressed between developing and differentiated skate and mammalian chondrocytes (Aim 1), and that may underlie arrest prior to hypertrophy in the former. ATAC-seq and comparative genomic approaches will then be used to test for variation in non-coding regions (i.e. putative enhancers) that might account for divergent gene expression during skate and mammalian skeletogeneis (Aim 2). Finally, skate-inspired molecular manipulations (CRISPR/Cas9 genome editing and/or transgenesis) will be incorporated in an in vitro model of mammalian skeletogenesis, in order to achieve a permanent and stable chondrocyte cell state from mammalian mesenchymal progenitors (Aim 3). This project will capitalize on the unique properties of the skate skeleton, and on the biological resources, facilities, and expertise that are available at the Marine Biological Laboratory in Woods Hole. By taking an evolution-inspired tissue engineering approach, this project will contribute to the development of novel in vitro techniques for cartilage engineering and for the treatment of mammalian skeletal pathologies.


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 = -$11,416 )
2026	2024	THE MARINE BIOLOGICAL LABORATORY	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	1/27/2026	NON-COMPETING CONTINUATION	-$11,416
														Subtotal = -$11,416

Issue Date FY: 2025 ( Subtotal = -$41,684 )
2025	2024	THE MARINE BIOLOGICAL LABORATORY	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	3/20/2025	NON-COMPETING CONTINUATION	-$41,684
														Subtotal = -$41,684

Issue Date FY: 2024 ( Subtotal = $76,756 )
2024	2024	THE MARINE BIOLOGICAL LABORATORY	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	8/7/2024	NON-COMPETING CONTINUATION	$76,756
														Subtotal = $76,756

Issue Date FY: 2023 ( Subtotal = $69,500 )
2023	2023	THE MARINE BIOLOGICAL LABORATORY	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	8/18/2023	NEW	$0
2023	2023	THE MARINE BIOLOGICAL LABORATORY	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	8/18/2023	NEW	$69,500
														Subtotal = $69,500

Grand Total All Awards = $93,156

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Molecular control of chondrocyte hypertrophy: an evolutionary approach

Award Number: F32AR082273

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: 09/01/2023

PERIOD OF PERFORMANCE END DATE: 01/06/2025

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