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Life Sciences Moment
UMass center charts faster path from bench to bedside
Hawk Moth and microRNA

Schwartz is investigating the molecular mechanisms that control muscle atrophy and death and has recently focused on the role of microRNAs, whose defects may serve as the basis of many diseases, including cancer.

 
The “hawk moth” was gifted with an extraordinary set of muscles and a radical maturation process. A research project spearheaded by biologist Lawrence Schwartz is revealing that on a cellular level that process bears a striking resemblance to what happens in the human condition sarcopenia; the progressive loss of muscle mass and strength associated with aging.

Schwartz, the Eugene M. and Ronnie Isenberg Professor of Integrated Science, has been mystified with the moth since he first studied it as a graduate student. Sarcopenia afflicted individuals ultimately lose a substantial amount of muscle mass, which leads to postural instability and hospital visits. The insect serves as an excellent model for the research because of the naturally occurring physiological process that precedes the emergence of the adult moth at the end of metamorphosis. During that time, 40 percent of the hawk moth’s muscle mass is lost. These muscles then activate programmed cell death and rapidly die. 

Schwartz is investigating the molecular mechanisms that control muscle atrophy and death and has recently focused on the role of microRNAs. First discovered in 1993 by Victor Ambros at the UMass Medical School, microRNAs have been shown to be key regulators of gene expression during development and homeostasis in cells. Defects in the expression of microRNAs may serve as the basis of many diseases, including cancer.

“If you can selectively regulate these processes, then you have much better tools for treating disease. Right now some of the tools that we use, especially for treating cancer, are not very cell-type specific and there can be a lot of collateral damage,” Schwartz explains.

Because Schwartz’s research holds promise for clinical application, his project was selected for support by the UMass Center for Clinical and Translational Sciences (UMCCTS), one of 55 centers in the United States funded by the NIH to accelerate the time it takes to translate clinical lab discoveries into treatments for patients. The project is one of eight awarded grants in 2012 through the center’s Moment Fund, seed money awarded to qualifying projects.

DISCOVERY DISCONNECT

The UMCCTS was founded in 2010 with a five-year renewable grant for $20 million from the NIH. The effort was launched after a 2008 study led by Despina Contopoulos-Ioannidis of the Stanford School of Medicine revealed the median time lapse between a research finding and its publication of use in highly-cited medical literature was 24 years—a conclusion that drew attention to an obvious disconnect between discovery and impact. John L. Sullivan, recently retired vice provost for research at UMass Medical School, was the founding PI for the project.

“In the past, researchers would conduct the basic science piece and assume that someone else would take care of the translation. You need a more deliberate strategy to ensure these discoveries move into practice,” explains Michael Malone, vice chancellor for research and engagement.

The UMass Medical School in Worcester is headquarters for the UMCCTS, yet the NIH grants are spread across the UMass system through the Moment Fund. Approved projects are set up as multidisciplinary collaborations between the UMass campuses and the medical school. To ensure the research is conducted in a way that facilitates greater efficiency and productivity in enhancing public health, the research groups are required to have at least one principal investigator (PI) or co-PI from the Worcester campus.

“If you’re not working collaboratively, you’re not shouldering the responsibility you have to move your discoveries into the clinic. The focus on translational sciences that NIH has been pushing helps academics think a little bit more broadly about that responsibility—and I think it makes for better science,” says Schwartz.

WORKING TOGETHER

Schwartz gathered research collaborators for his sarcopenia study while taking his sabbatical at the UMass Medical School. Collaborators include William Theurkauf, molecular medicine and Zhiping Weng, biochemistry and molecular pharmacology at UMass Medical and Priscilla Clarkson, dean of Commonwealth Honors College, who leads the Muscle Biology and Imaging Lab at UMass Amherst. Schwartz arranged the team with clinical advancement in mind and says it is his duty to act in alignment with the national initiative put forth by the NIH.

Schwartz’s colleague Joseph Jerry is working on another recently funded project that delves into the gene expression signatures in relation to atypical hyperplasia (premalignant breast lesions). Jerry, a veterinary and animal scientist, is well known for his work with breast cancer and leadership of the Pioneer Valley Life Sciences Institute (PVLSI), a partnership between Baystate Medical Center in Springfield and UMass Amherst that brings together leading researchers and clinicians from both institutions to study cancer, diabetes, and a range of other human diseases. The Moment Fund grant will help Jerry and his fellow collaborators to deepen their understanding of pre-malignancy. They are working on profiling the various subtypes of the disease in order to detect the 20 percent of women diagnosed with atypical hyperplasia who will likely develop breast cancer so they can be treated to prevent cancer.

HIGH IMPACT

Veterinary and animal scientist Lisa Minter is wrapping up work on her Moment Fund grant, a high-impact project with UMass Medical School collaborators Alonzo Ross and Phillip Zamore, biochemistry and molecular pharmacology. Ross had approached Minter about her immunological studies to ask that she join him in a search for more successful therapies for glioblastoma—the highly invasive brain tumor referred to as “uniformly lethal.” Because of the way glioblastoma develops in the brain, the tumors are virtually impossible to remove surgically and are often not responsive to chemotherapeutic treatments, making the disease a prime target for translational research.

Ross was particularly interested in experimenting with a protein inhibitor that Minter was working on. The inhibitor serves to block Notch—a sometimes pro inflammatory protein associated with a large number of cancers and autoimmune disorders. Notch has long perplexed researchers because it is highly pleotropic, meaning it produces variable outcomes.

“Notch has very contextual signaling and that’s part of what makes it so challenging to study. But it’s also what makes it so interesting to study because you have to take a step back, look at your system, and really take a broad view,” Minter explains.

By looking at the entire process of Notch signaling and its subsequent effects on microRNA regulation, the team aims to develop a treatment strategy for glioblastoma that drastically reduces tumor growth when used in conjunction with standard chemotherapeutics. Not only does this have a huge impact for glioblastoma patients, but the results may hold vast potential in treating other types of cancer.

“There’s a lot of interest in targeting Notch, because it does seem to be over expressed or aberrantly expressed when it shouldn’t be, in many different types of cancers,” Minter says.

“The UMCCTS provides a wonderful vehicle for facilitating collaborations between basic and clinical researchers across the UMass system” say Schwartz. “This will result in more creative science and enhance our ability to provide new diagnostic and therapeutic tools for the public.” 

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