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NIAMS Awards $500K in Three Grants for miRNA Research in Skeletal Development, Disease


By Doug Macron

The National Institute of Arthritis and Musculoskeletal and Skin Diseases last month awarded nearly $500,000 to fund three grants supporting researchers studying the role of microRNAs in skeletal development and disease.

The first grant went to University of Texas Southwestern Medical Center researcher Douglas Millay to support his investigation of the role miR-206 plays in skeletal muscle regeneration.

"Skeletal muscle possesses the ability to regenerate after injury and grow postnatally through the activation of satellite cells," he wrote in the grant's abstract. Yet the molecular mechanisms controlling satellite cell function are not well understood.

"Recently, it has been revealed that miRNAs, which negatively regulate gene expression by promoting mRNA degradation and inhibiting mRNA translation, function in the stress response of muscle cells and play important roles in muscle development and disease," Millay, a postdoctoral fellow in the lab of Eric Olson, noted.

The Olson lab has identified nine miRNAs that are up-regulated and 20 that are down-regulated after cardiotoxin-induced skeletal muscle injury, and "we plan to investigate the role of a number of these miRNAs in the regenerative process," he wrote. Particular attention will be paid to miR-206, which is "dramatically induced" following cardiotoxin injury.

Mice lacking miR-206 have already been generated and are viable, he added, and they "exhibit no gross abnormalities in skeletal muscle. Using these mutant mice, we will assess the role of miR-206 in regeneration and elucidate the downstream effectors which mediate this response."

The research "will provide new insights into the pathophysiology of muscle disease and regeneration, and should also facilitate the development of new therapeutic strategies for muscle repair through the manipulation of miRNA expression and function," he concluded.

Millay's grant, which began on April 1 and is worth $50,474 in the first year, is set to end March 31, 2013.

The second grant was awarded to Jason O'Rourke, also a postdoc in Olson's lab, to fund his work looking at the role of miR-29 in postnatal skeletal muscle development and disease.

"Skeletal muscle atrophy is a debilitating disorder that is characterized by profound muscle wasting during adulthood," often as a result of myopathic diseases such as amyotrophic lateral sclerosis, cancer, and AIDS, he wrote in the grant's abstract.

"Although it is clear that skeletal muscle wasting is caused by defects in postnatal muscle development and maintenance, the precise molecular mechanisms controlling myogenesis after birth are poorly understood, and effective therapies to treat muscle atrophy are lacking," he added.

To address this issue, he is investigating the role miRNAs play in skeletal muscle development, and whether drugs that either inhibit or mimic the small non-coding RNAs can serve as therapeutics for muscle-wasting disorders.

Data showing that miR-29 is postnatally regulated and becomes most abundant as skeletal muscles reach their maximum mass suggests that it could play a role in maintaining skeletal muscle homeostasis during adulthood, he wrote.

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"This hypothesis will be tested by characterizing postnatal muscle development in miR-29 skeletal muscle-specific gain-of- and loss-of-function transgenic mice," the abstract states, while mice either over-expressing or lacking the miRNA will be used to identify the mRNAs and biochemical pathways that are regulated by miR-29 during post-natal skeletal muscle development.

O'Rourke and his colleagues will also follow up on the finding that levels of the miRNA are elevated at very early stages of denervation-induced skeletal muscle atrophy, which suggests that miR-29 promotes muscle wasting.

Specifically, the possibility that miR-29 inhibition may protect against muscle atrophy will be tested by determining if mice lacking the miRNA in muscle are resistant to injury-induced skeletal muscle atrophy, according to the grant's abstract. If they are, a drug silencing miR-29 may have therapeutic potential.

O'Rourke's grant began on April 1 and is worth $47,606 in its first year. It will run through the end of March 2013.

The last grant was awarded to Massachusetts General Hospital's Tatsuya Kobayashi to fund his research into the role miRNAs play in mammalian skeletal development, specifically in mice.

"Our findings in Dicer-deficient mouse growth plates lead to our central hypothesis that chondrocytic miRNAs regulate cell proliferation and differentiation," he wrote in his grant's abstract. In early 2008, Kobayashi and colleagues reported in the Proceedings of the National Academy of Sciences that Dicer-null growth plates showed a "progressive reduction in the proliferating pool of chondrocytes, leading to severe skeletal growth defects and premature death of mice."

"However, because Dicer is known to process RNA species other than miRNAs, it is not clear to what extent the loss of miRNAs contributes to the phenotype of Dicer-deficient chondrocytes," he added in the abstract.

With funding from NIAMS, he aims to "confirm the role of miRNAs in regulation of chondrocyte proliferation and differentiation by generating and analyzing conditional knockout mice missing DGCR8 and Drosha to eliminate miRNAs independently of Dicer," according to the abstract.

Additionally, to understand how miRNAs regulate chondrocyte proliferation and differentiation, he and his team will "experimentally identify miRNA-regulated transcripts in chondrocytes by profiling Ago2-associated RNAs," then characterize proliferation defects in miRNA-deficient chondrocytes using flow cytometry.

Lastly, Kobayashi will investigate the role of two chondrocyte-specific miRNAs — miR-140 and miR-140* — in skeletogenesis. The gene encoding these miRNAs is evolutionarily conserved in vertebrates, which suggests it has a role to play in the skeletal system, he noted.

Knockout mice lacking this gene will be generated and characterized, while target transcripts of the miRNAs will be experimentally identified. "Defining roles of miRNAs and identifying their targets in chondrocytes may lead to identification of novel therapeutic targets for skeletal disease intervention," he wrote.

Kobayashi's grant began on April 1 and is worth $393,520 in its first year. It will run until March 31, 2015.

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