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Genome and epigenome editing of induced pluripotent stem cells for investigating osteoarthritis risk alleles

Award Number: R21AR080409
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: 09/22/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2024

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Genome and epigenome editing of induced pluripotent stem cells for investigating osteoarthritis risk alleles - Abstract Genome wide association studies (GWAS) in large cohorts have identified and replicated robust single nucleotide polymorphisms (SNPs) with a strong association to osteoarthritis (OA) development. While many SNPs have been identified as risks for OA development, a mechanistic understanding of their role in cartilage homeostasis and mechanobiology has remained elusive. We propose to use a novel in vitro system combining genome editing of human induced pluripotent stem cells (iPSCs) and cartilage tissue engineering for studying the functional effect of identified OA SNPs on the biochemical and mechanical properties of articular cartilage. In preliminary data, we reported a functional characterization of rs11780978 in which we identified an expression quantitative trait locus (eQTL) operating on the gene PLEC in the cartilage of patients with OA. Our primary hypothesis is that OA-associated SNP rs11780978 results in reduced expression of PLEC in chondrocytes secondary to altered epigenetic regulation at this locus. Using CRISPR-Cas9 and dCas9TET-mediated genome editing, we will examine the role of genetic and epigenetic modulation (PLEC knockout and hypomethylation of the functional region) on the chondrogenic differentiation of hiPSCs. Furthermore, we propose that reduced production of plectin due to this SNP alters the response of chondrocytes to mechanical stress under physiologic or pathologic conditions. This tissue-engineering approach provides a model system that can be used in future studies to examine specific mechanistic hypothesis on the link between OA-associated SNPs and the regulation of chondrocyte physiology. Identification of these mechanisms will hopefully lead to new therapeutic targets for preventing or slowing OA progression.


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 = $171,050 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	9/14/2023	NON-COMPETING CONTINUATION	$171,050
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	2	9/20/2023	NON-COMPETING CONTINUATION	$0
2023	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	9/19/2023	NEW	$0
														Subtotal = $171,050

Issue Date FY: 2022 ( Subtotal = $207,460 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/20/2022	NEW	$207,460
														Subtotal = $207,460

Grand Total All Awards = $378,510

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Genome and epigenome editing of induced pluripotent stem cells for investigating osteoarthritis risk alleles

Award Number: R21AR080409

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: 09/22/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2024

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