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The role of microRNAs in cartilage homeostasis and osteoarthritis arthritis treatment

Award Number: R01AR050631
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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ABSTRACT Chondrocytes play an important role in limb development, postnatal skeletal growth and in maintaining cartilage tissues during adult life. Dysregulation of gene expression in chondrocytes is a key event in the pathogenesis of osteoarthritis (OA). MicroRNAs are a family of noncoding RNAs that are evolutionarily conserved and regulate gene expression by posttranscriptional mechanisms. Many miRs show tissue specific expression patterns, suggesting that these miRs play a crucial role in tissue specific physiological or developmental processes. However, chondrocyte specific miRs, their upstream molecular signals, and target genes are only beginning to be identified. We and others reported that miR-140, a cartilage specific miRNA, plays a critical role both in cartilage development and homeostasis while the reduced expression in OA contributes to pathogenesis. In our preliminary experiments, both strands of miR-455 (miR-455-5p and miR-455-3p) as well as miR-140 were identified as targets of Sox9, a main transcription factor for cartilage specific genes. Expression of miR- 455-5p/3p was down-regulated in human OA cartilage compared with normal cartilage. Using CRISPR/Cas9 system, we generated miR-455-5p/3p knockout mice. These mice showed a severe OA phenotype at 6 months. Microarray analyses revealed a set of possible miR-455 target genes in chondrocytes, including HIF2A, which is a key transcription factor in OA pathogenesis, and a target of both strands of miR455. Importantly, HIF2A was strongly increased in almost all chondrocytes in articular cartilage of miR-455 null mice at 6 months. These observations support the hypothesis that miR-455-5p/3p are critical regulators of cartilage homeostasis and that changes in their expression and function play an important role in diseases affecting articular cartilage. We propose the following specific aims: Aim 1: Analyze the function of miR-455-5p/3p in OA pathogenesis using miR-455 KO mice and human articular chondrocytes. Aim 2: Identify in articular chondrocytes the direct miR-455-5p/3p downstream targets that regulate cartilage homeostasis and OA pathogenesis. Aim 3: Examine the therapeutic effects of intraarticular miR-455s administration in animal models of OA. The proposed studies have the potential to reveal important new regulatory pathways that control cartilage development and homeostasis and open new insight on disease mechanisms and therapeutic interventions.


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 = $0 )
2023	2021	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	15	11/2/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $410,795 )
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	15	4/20/2021	NON-COMPETING CONTINUATION	$410,795
														Subtotal = $410,795

Issue Date FY: 2020 ( Subtotal = $423,500 )
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	14	3/31/2020	NON-COMPETING CONTINUATION	$42,350
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	14	2/27/2020	NON-COMPETING CONTINUATION	$381,150
														Subtotal = $423,500

Issue Date FY: 2019 ( Subtotal = $423,500 )
2019	2019	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	13	4/3/2019	NON-COMPETING CONTINUATION	$423,500
														Subtotal = $423,500

Issue Date FY: 2018 ( Subtotal = $423,500 )
2018	2018	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	12	5/9/2018	NON-COMPETING CONTINUATION	$42,350
2018	2018	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	12	2/27/2018	NON-COMPETING CONTINUATION	$381,150
														Subtotal = $423,500

Issue Date FY: 2017 ( Subtotal = $423,500 )
2017	2017	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	11	3/17/2017	COMPETING CONTINUATION	$423,500
2017	2017	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	11	2/22/2017	COMPETING CONTINUATION	-$423,500
2017	2017	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	11	2/21/2017	COMPETING CONTINUATION	$423,500
														Subtotal = $423,500

Issue Date FY: 2014 ( Subtotal = $401,980 )
2014	2014	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	10	6/23/2014	NON-COMPETING CONTINUATION	$401,980
														Subtotal = $401,980

Issue Date FY: 2013 ( Subtotal = $389,675 )
2013	2013	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	9	5/10/2013	NON-COMPETING CONTINUATION	$389,675
														Subtotal = $389,675

Issue Date FY: 2012 ( Subtotal = $410,184 )
2012	2012	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	8	5/21/2012	NON-COMPETING CONTINUATION	$410,184
														Subtotal = $410,184

Issue Date FY: 2011 ( Subtotal = $410,184 )
2011	2011	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	7	5/20/2011	NON-COMPETING CONTINUATION	$410,184
														Subtotal = $410,184

Issue Date FY: 2010 ( Subtotal = $427,275 )
2010	2010	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	4/16/2010	COMPETING CONTINUATION	$427,275
														Subtotal = $427,275

Issue Date FY: 2008 ( Subtotal = $320,477 )
2008	2008	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	3/27/2008	NON-COMPETING CONTINUATION	$320,477
														Subtotal = $320,477

Issue Date FY: 2007 ( Subtotal = $323,912 )
2007	2007	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	3/30/2007	NON-COMPETING CONTINUATION	$323,912
														Subtotal = $323,912

Issue Date FY: 2006 ( Subtotal = $333,586 )
2006	2006	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	3/28/2006	NON-COMPETING CONTINUATION	$333,586
														Subtotal = $333,586

Issue Date FY: 2005 ( Subtotal = $341,614 )
2005	2005	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	4/10/2005	NON-COMPETING CONTINUATION	$341,614
														Subtotal = $341,614

Issue Date FY: 2004 ( Subtotal = $341,614 )
2004	2004	SCRIPPS RESEARCH INSTITUTE, TPC 7	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	6/29/2004	NEW	$341,614
														Subtotal = $341,614

Grand Total All Awards = $5,805,296

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The role of microRNAs in cartilage homeostasis and osteoarthritis arthritis treatment

Award Number: R01AR050631

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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