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Laura Calvi, M.D., achieved what a lot of translational researchers only dream of: For years, she made important discoveries in the lab, but then she was able to turn the project into a clinical trial, where it has begun to benefit patients.

"It's an amazing accomplishment to get this far," says Calvi, a co-leader of Wilmot Cancer Institute's Cancer Microenvironment research program.

Many researchers, of course, intend for their basic science to eventually help patients. But the process can get derailed during the years it takes to develop goals, run experiments, publish the results, and then design and fund clinical trials. Sometimes good ideas don't pan out, or funding is lost, or the scientist gets pulled in other directions.

In this case, though, a strong team approach made it happen. Calvi emphasized that moving the laboratory project into the clinical trial required a close collaboration with many Wilmot clinician-scientists, including Jane Liesveld, M.D.; Jason Mendler, M.D., Ph.D.; Michael Becker, M.D.; Frank Akwaa, M.D.; and Melissa Loh, MBBCh.

"This project represents a huge success," Calvi says. "To hand off a concept to a clinical team that can run a study — it's really, really difficult, but we've done it."

The Annual Center for Musculoskeletal Research Symposium has been a celebrated training-related CMSR tradition for the past 10 years.

This year, our Annual Center for Musculoskeletal Research (CMSR) symposium is going virtual due to restrictions of COVID-19. As in years past, the virtual symposium features a scientific session with podium presentations by several predoctoral and postdoctoral trainees selected based on refereed abstracts, a poster session for all trainees in the CMSR, and a spotlight session featuring the new CMSR faculty and a special guest of honor (Dr. Randy Rosier), followed by a celebration social hour to promote comradery and interaction between past and current members of the CMSR. The highlight of the symposium is the awarding of 3 Trainee Travel Awards to recognize their outstanding research presentation in the Scientific Session.

Too often, promising therapeutic drug candidates that are developed as a result of expensive animal studies prove ineffective—or even dangerous—when tested in humans. Although lab animals may have similar anatomical features to humans, their physiology, metabolism, and genetic diversity can be quite different.

Three University of Rochester biomedical researchers are addressing the problem through a novel form of personalized medicine. They are developing an alternative "organ on a chip" technology that uses tissue samples from an individual human patient to mimic how a disease or disorder might occur in that patient—in this case, scarring from a tendon injury, especially after surgery to repair the damage.

The technology, using a novel integration of ultrathin nanoporous membranes and photonic sensors, would allow clinicians to better predict whether a patient is likely to develop debilitating scar tissue, and if so, to then determine which therapeutic drug will work best for that patient.

"This technology is likely the future of medicine. You can now think about personalized medicine in a chip," says Hani Awad, the Donald and Mary Clark Distinguished Professor in Orthopaedics and professor of biomedical engineering at the Center for Musculoskeletal Research. He is collaborating on the project with James McGrath, professor of biomedical engineering, and Benjamin Miller, professor of dermatology, biomedical engineering, optics, and biochemistry and biophysics.

The collaboration—aided by the close proximity of the University of Rochester Medical Center and its Center for Musculoskeletal Research to the Department of Biomedical Engineering at the nearby River Campus—represents "an exquisite blend of biological science and engineering," Awad says. "The team outside the three of us includes sensor scientists, orthopedic surgeons, and immunologists. It's a very multidisciplinary approach."

Clinical Trials on a Chip researchers plan to build and test common and rare disease models to help improve the clinical trial process.

Approximately 85% of late-stage clinical trials of candidate drugs fail because of drug safety problems or ineffectiveness, despite promising preclinical test results. To help improve the design and implementation of clinical trials, the National Institutes of Health has awarded 10 grants to support researchers' efforts in using tiny, bioengineered models of human tissues and organ systems to study diseases and test drugs. One major goal of the funded projects is to develop ways to better predict which patients are most likely to benefit from an investigational therapy prior to initiating clinical trials.

The awards total more than $6.9 million in the first year, and approximately $35.5 million over five years, pending available funds. They are administered through a new program, Clinical Trials on a Chip, which is led by NIH's National Center for Advancing Translational Sciences (NCATS) in conjunction with several other NIH Institutes and Centers, including the National Cancer Institute, the National Institute of Child Health and Human Development, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Tissue chips, or organs-on-chips, are 3-D platforms engineered to support living human tissues and cells and mimic complex biological functions of organs and systems. Tissue chips are currently being developed for drug safety and toxicity testing and disease modeling research, including on the International Space Station. Clinical Trials on a Chip is one of several initiatives that are a part of the NCATS-led Tissue Chip for Drug Screening program, which was started in 2012 to address the major gaps in the drug development process.

Research scientists aren't born, they're made -- and it doesn't happen overnight. A critical factor in their early development: seed funds to launch their own research projects.

Federal and University of Rochester-sourced funds help young researchers at CMSR build skills in scientific investigation, writing research papers and grant proposals, and presenting their work. A relatively modest investment in promising researchers yields big returns for them.

A core belief of the CMSR is that outstanding New/Early Stage Investigators (N/ESI, defined by NIH as faculty who have not received a large independent research grant) who gain access to pilot research funding, and state-of-the-art research equipment, will produce the preliminary data necessary to support their NIH R01 and K-award applications, and establish themselves as independent investigators and national leaders in their respective field. Evidence that the CMSR is excelling with this primary mission comes from the remarkable 42-fold return on investment (ROI) on its NIH P30 Core Center Pilot Program. The CMSR extended a total of $500K in pilots from 2014-2018 ($100K per year, approximately $22.7K per award to 24 awardees, including 2 applicants that only received Research Core support, but no budget).

These pilots catalyzed $21,169,818 in extramural funding from NIH and other agencies (direct cost only) to date. Beyond the financial ROI, the pilots enabled 62 publications and resulted in 17 faculty promotions. To add to its P30 Pilot Program, the CMSR plans to award $30K from a new Discovery Fund (awards up to $5,000 to be used in the CMSR's Research Cores), which will be expeditiously awarded by the CMSR's Mentoring Core without a formal grant application or review process.

"At a time when federal funding for investigations is at a premium -- and when many young researchers choose industry over academic research -- every dollar matters so much," said Edward Schwarz, Ph.D., Richard and Margaret Burton Distinguished Professor of Orthopaedics and Director of CMSR. "P30 funding enables our researchers to move from collaborating on our PIs' research projects, to working independently and developing autonomy, discipline, experience and professional networks that will serve them over the course of their careers, and help us develop research scientists for the future."

COVID-19 precautions forced CMSR investigators to temporarily spend some or most of their work days offsite and away from the lab, but its culture -- and technology -- ensured that scores of active research projects didn't skip a beat -- and even launched new research related to COVID-19 itself.

CMSR reengineered its workflows as COVID-19 cases peaked in western New York in early spring, in response to University of Rochester Medical Center and New York state social distancing guidelines designed to prevent the spread of the virus. URMC sent hundreds of workers work off-site to reduce the risk of transmission on its campus.

The team of 140 CMSR researchers, who are used to working collaboratively in their lab space on URMC's campus, quickly adapted to the disruption in standard research practice. Everyone at CMSR worked off-site for some or most of their work time.

The change was dramatic, but the CMSR culture that encourages fluid and creative collaboration made the transition easier, according to Edward Schwarz, Ph.D., Richard and Margaret Burton Distinguished Professor of Orthopaedics and Director of CMSR. "We have 12 research labs in the CMSR, but no silos. Investigators from different labs are encouraged to work collaboratively within their own teams, and with extended CMSR team members."

Where are tomorrow's biomedical research scientists coming from, and where are they going? It's a question on the minds of everyone in academic biomedical research. Despite a record high cadre of PhD graduates flooding the field in the U.S. today, most grads skip academic research career paths in favor of industry jobs. The trend is nearly two decades old, and is creating a shortfall in researchers to elucidate the root causes of disease and develop new treatments.

But there are some encouraging exceptions, and reason to hope there's a way to entice talented researchers back to academia. The University of Rochester's Center for Musculoskeletal Research (CMSR) recently restructured its training program to attract and mentor the nation's most promising biomedical researchers with the potential to become independent investigators at major medical centers -- and its 2019-2020 class suggests it's on to something: 10 graduates out of a class of 14 chose academic postdoctoral research fellowships. By comparison, the center never had more than two graduates in a given year choose academic destinations. (The 10 academic research graduates: Richard Bell, PhD; Sarah Catheline, PhD; Madison Doolittle, PhD; Christopher Farnsworth, PhD; Margaret Freeberg, PhD; Corey Hoffman, PhD; Alexander Kotelsky, PhD; Jinbo Li, PhD; Xi Lin, PhD; Robert Maynard, PhD; Laura Shum, PhD; and Ryan Trombetta, PhD.)

Like other research centers around the country, two years ago the CMSR lost its NIH T32 training grant that had supported PhD student education and research over the last decade, due to the large proportion of funded trainees who chose industry over an independent research career. In April 2020, CMSR's efforts to restructure its Rochester Musculoskeletal (ROCMSK) Training Program paid off with a new 5-year T32 grant for $2.4 million, which will be directed by Drs. Hani A. Awad, Laura M. Calvi and Danielle S.W. Benoit.

Osteoarthritis, or OA, is the most common cause of disability among adults, and is a significant public health burden since there is currently no treatment to prevent disease progression following the onset of symptoms. While OA is primarily characterized by a loss of articular cartilage, it also affects all tissues within the joint including bone, meniscus and synovium. The result is disabling pain and loss of mobility requiring many patients to eventually undergo total joint replacement

Historically, OA has been attributed to "wear and tear" in response to mechanical load over time. More recently, OA is understood to be an active disease process involving altered tissue metabolism and local inflammation. Advanced age is the most important risk factor for the development of OA, however, the mechanisms driving the onset of disease during the aging process are unclear and understudied. Thus, to better understand how the aged joint environment is predisposed to the onset of OA, Dr. Jennifer Jonason's laboratory in the CMSR is investigating whether the cartilage-producing chondrocytes themselves, are the primary source of factors that lead to cartilage degradation and inflammation in age-related OA.

Articular chondrocytes are a long-lived, quiescent cell population that experiences increased oxidative stress with age, and oxidative stress can cause DNA damage in the form of double-strand breaks (DSBs). DNA DSBs, in turn, can activate NF-κB and Interferon Regulatory Factor (IRF) transcription factors via a protein known as Stimulator of Interferon Gene, or STING, resulting in expression of proinflammatory cytokines and chemokines that drive an innate immune response. Dr. Jonason's lab has found evidence that aged articular chondrocytes have DNA DSBs as well as increased activation of both NF-κB and IRF transcription factors. Further, the lab has found that activation of NF-κB signaling specifically in chondrocytes can accelerate the onset of an early stage age-related OA phenotype in mice.

To continue this work, Dr. Jonason will receive a 5-year grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. The ~$2M grant will support further study on the role of DNA DSBs in articular chondrocyte fate and OA development, as well as defining the specific mechanisms by which DNA DSBs induce NF-κB and IRF transcription factors in chondrocytes leading to their development of a proinflammatory secretory phenotype. These studies will also determine whether inhibition of STING could be a novel approach to prevent NF-κB signaling and OA onset in aging joint tissues, thus, adding important clinical relevance to this highly mechanistic project

The Center for Musculoskeletal Research continues to be among the best represented at the Annual Meeting of the Orthopedic Research Society (ORS). The 2020 meeting took place in Phoenix, Arizona Feb 8-11, 2020.

The CMSR had more than 30 scientists presenting work at the meeting, including podium presentations from CMSR Trainees: Anne Nichols (Loiselle Lab), Gowri Muthukrishnan (Schwarz Lab), Yugo Morita (Schwarz Lab), Katie Best (Loiselle Lab), Mark Ninomiya (Schwarz Lab), Keshia Mora (Buckley & Loiselle Labs), Phong Nguyen (Kuo Lab). The excellent work by CMSR trainees was further highlighted as Katie Best (Loiselle Lab) and Keshia Mora (Buckley & Loiselle Labs) received Podium Presentation Awards from the ORS Tendon Section, while Anne Nichols (Loiselle Lab) received an Education Grant from the OrthoRegeneration Network, and Yugo Morita (Schwarz Lab) was a finalist for a New Investigator Recognition Award (NIRA).

The Ralph C. Wilson, Jr. Foundation has awarded a grant of $460,000 to upgrade and repurpose the city-owned stadium at 460 Oak Street for use as a youth sports training facility and sports complex. The concept for the Rochester Community Sports Complex includes making the former soccer stadium available for various sporting and community events and renovating the adjacent 25,000 square-foot building into an indoor training facility — the first in Rochester. Planners envision it will be used by Rochester City School District athletic teams, community sports teams and clubs, community health and fitness professionals, and city residents. "This truly is about leveling the playing field," says Mayor Lovely A. Warren. "With no access to indoor training facilities nearby or athletic trainers who can help with injury prevention, student athletes in Rochester are at a competitive disadvantage. The Rochester Community Sports Complex will address this inequity."