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Dr. Matthew Gentry

Video: UK scientist explains his unique path to studying disease

When UK researcher Matthew Gentry began his career studying the biology of plants, he didn’t realize he’d someday be pursuing a cure for a human disease.

“You have to be willing to go where the science takes you,” says Gentry, a professor in the UK College of Medicine.

In Gentry’s case, the journey began when he found that a certain plant protein behaved similarly to the human protein that plays a role in Lafora disease – a rare congenital neurodegenerative condition that causes severe epilepsy, loss of speech and muscle control, and dementia, eventually leading to death.

This discovery provided information that medical researchers around the world are using today to test potential therapies for this deadly disease.

The research was also a step toward the development of methods to modify starch, with applications in the manufacturing of products such as plastics, animal feed, glue and clothing.

On a molecular level, the overlap between plant and human biology is tremendous, Gentry explains.

“Not long ago, the prevailing thought was that you could either work to cure a disease or you could work to figure out how something [a plant, a cell] functions,” Gentry says. “We are now at the point where the two intersect.”

Gentry spends much of his time advocating for more science funding through his work with the American Society for Biochemistry and Molecular Biology. The current funding landscape is such that scientists must spend more and more of their time writing grants, which takes them away from doing meaningful research, he explains.

He also hopes that more of this funding will support the types of basic research that shed light on cellular function and dysfunction.

“This type of research can have implications for many diseases, not just one,” he says. “We need to be careful not to silo all the research dollars for specific diseases because that sometimes doesn’t allow the best science to get done.”

Watch the video below to learn more about Dr. Gentry’s innovative research.


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Research featuring UK scientists shows promise in treating cancer

A new study published in Nature Chemical Biology featuring UK research highlights a promising new way to address lung cancer and other deadly diseases.

Lung cancer accounts for 25 percent of cancer deaths in the U.S., and one out of every two patients diagnosed with lung cancer won’t survive more than one year. The problem is at its worst in Kentucky, where the state continues to lead the nation in lung cancer incidence and death.

The new research brings together scientists from the UK College of Pharmacy, Memorial Sloan Kettering Cancer Center and St. Jude Children’s Research Hospital and reveals a new way to treat lung cancer by blocking cancer-causing proteins on a cellular level. The study involves a compound developed by UK College of Pharmacy Dean Kip Guy’s lab.

The foundation for research

The groundwork for the study began more than 10 years ago when Dr. Bhuvanesh Singh, a physician-scientist at Memorial Sloan Kettering Cancer Center, identified that an increase of a protein called DCN1 led to more malignant lung cancers and shorter life spans for his patients. Of the patients he studied, those with high levels of DCN1 succumbed to the disease more quickly than those with normal levels.

Frustrated by their findings, Singh’s team set out to study the specifics of DCN1. While DCN1 is a normally occurring protein, his team found that too much of it leads directly to cancer formation. Simply put, a malignant tumor was formed when the amount of DCN1 in a cell was increased. Thus, patients with more DCN1 got sick more quickly and died faster than their counterparts.

Efforts in Brenda Schulman’s lab at St. Jude, led by biochemist Daniel Scott, established how DCN1 interacts with other proteins and controls cellular processes. Their key discovery used X-ray crystallography to show that a small modification of the partner protein to DCN1, known as UBE2M, was required for DCN1 to work. This common modification, N-terminal acetylation, had not previously been shown to be critical to controlling activity of this specific protein. Recognizing the potential for targeting this modification, Shulman reached out to form a collaboration between the three laboratories.

Their goal: to develop a way to stop DCN1 from killing patients.

‘Jamming the lock’

Understanding the behavior and function of DCN1 was far more ambitious than running simple tests. It was a significant step forward in understanding how proteins within a cell work.

Building upon the science from Shulman’s team, Jared Hammill from Guy’s lab and Danny Scott from Schulman’s lab worked to stop the interactions of DCN1 altogether. If DCN1’s activity depended on this interaction, then it stood to reason they could create a compound to intervene and stop the interaction from happening.

Guy describes the interaction as a “lock and key model.” Scientists have a blank key – which is UBE2M – and a lock, which is DCN1. The key wants to fit into the lock, so it’s modified until it fits. This modification process is N-terminal acetylation.

“What’s the significance?” Guy said. “Well, we’re the first people to show that protein interaction controlled by N-terminal acetylation can be blocked. We’re essentially jamming the lock with a compound so the key won’t fit.”

The items jamming that lock are a series of small molecules created in the lab. When the molecules were tested directly in cancer cells, they worked. They effectively blocked DCN1 from binding to UB2EM. After decades of collaborative research, there was finally a barrier between lock and key.

What it means for patients

The impact of these findings for healthcare and lung cancer patients specifically could be profound.

“We are excited about the implications of this research, which offer us a meaningful solution for addressing diseases like cancer, neurodegenerative disorders and infection,” Shulman said. “It’s exciting to collaborate with so many complementary groups of expertise and to watch how Dr. Scott and Dr. Hammill led the team. This research opens many new doors for us.”

The collaboration between these three labs could mean relief to many of those suffering from a variety of diseases.

“To have spent decades on this research and have such promising results is truly exhilarating,” Singh said. “At the end of the day, what matters most is improving health outcomes for our patients. This work represents a very important step towards developing a new approach to treat the most difficult of cancers and hopefully increase cure rates.”

This research was funded in part by National Institutes of Health, the Howard Hughes Medical Institute and American Lebanese Syrian Associated Charities.


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RB2

UK’s new research facility will target Kentucky’s health concerns

Lisa Cassis

Lisa Cassis, PhD, UK vice president for research

Written by Lisa Cassis, PhD, UK vice president for research.

If you’ve driven along Virginia Avenue in Lexington, toward the main UK campus, you’ve probably seen the steel skeleton of the new research building under construction. This is Research Building 2, or RB2, a precious resource and a vehicle for UK to reduce the health disparities that most impact Kentucky.

This building will house researchers that focus on the following health disparities: cancer, obesity, diabetes, cardiovascular diseases and stroke, and substance abuse. These conditions have a major adverse impact on the health of Kentuckians, contributing to death rates from each disease that rank within the top 11 states in the nation.

RB2 will enable multidisciplinary research that approaches these disparities from numerous fields and perspectives healthcare researchers (both basic and clinical), public health, behavioral sciences, agriculture outreach and extension, economics, and engineering working in close proximity and collaboratively to develop solutions to these complex problems.

This $265-million building (funded half from the state of Kentucky, half from university resources, including private gifts) is scheduled to open in summer of 2018.

Thoughtful design and collaboration

The design of this modern research facility embodies a lifestyle that reduces health disparities, including a healthy food choice restaurant, a room to house bicycles for travel to and from the facility, and prominent staircases to encourage physical activity.

Within the laboratories, the design and focus comes with a specific scientific underpinning: Much of discovery today, whether at the cellular or community level, happens at the intersection of disciplines. By placing investigators together in “neighborhoods,” this facility is designed to foster discovery and collaboration so that what happens in the course of basic research can be translated to answers and solutions at the community level.

When researchers who are working on the same problem say, cancer but from different angles (economics, biomedicine, public health), work next to each other in a single building, it facilitates communication and promotes new avenues for problem solving. Through this design, the project will improve the lives of Kentuckians by providing modern space that lends itself to multidisciplinary research that is needed to address entrenched health problems.

Tackling Kentucky’s worst problems

While each of these major diseases influence citizens across the Commonwealth, they are of immense concern to our citizens residing in rural Appalachia, a region with some of the most pronounced rates of chronic diseases in the country.

A recent report from the University of Washington showed rates of death from cancer in the United States dropped by 20 percent between 1980 and 2014. However, these gains were not distributed equally across the country. Clusters of high mortality were found in many states, including Kentucky.

Four main factors are thought to drive these disparities: socioeconomic status, access to healthcare, quality of available healthcare and prevalence of risk factors, such as smoking, obesity and lack of physical activity. The Appalachian region of Kentucky experiences a perfect storm of these factors driving disparities.

A primary focus of research within the new building will be determining factors that drive more disease risk and burden in Appalachia, and developing preventive and therapeutic approaches that are optimized to have greater benefit to those living in this region.

Harnessing our strengths

RB2, the Biological Biomedical Research Building and the Lee T. Todd Jr. Building will be linked in complex, to further foster collaborative and multidisciplinary research. The connecting conduit building, serving as the spine of the complex, has been named the Appalachian Translational Trail, as it will house the nucleus of translational researchers who bring together all disciplines.

The real power of research is realized in bringing different groups of experts together, and in order to tap into that power, we applied a multidisciplinary approach to the planning of this new building. We began by aligning our work with the goals of UK’s 2015-2020 Strategic Plan. These goals invest in UK’s existing strengths and areas of growth in selected focus areas that benefit and enrich the lives of the citizens of the Commonwealth; recruit and retain outstanding faculty, staff and students; improve the quality of the research infrastructure across campus; and strengthen engagement efforts and translation of research. The planning and implementation of RB2 touches on each of these goals.

The health disparities we are targeting are areas of current UK strength in research and healthcare. We have strong individual investigators across all colleges at UK, as well as existing collaborative research centers that can bring intensified focus in these areas. We’ve tapped these experts, based on thematic areas in each of these health disparities, to use data to evaluate our current resources and identify areas in which we could strategically invest to expand resources and hire new investigators, who will most likely be housed within RB2, to make the biggest impact for Kentucky.

By growing our research enterprise to focus on the most critical health needs of Kentucky, we can translate basic science findings to clinical practice and to the community to fight these devastating health disparities and improve the quality of life for Kentuckians. We thank Kentucky legislators for their support of RB2, and we will do everything in our power through this precious resource to make that difference.


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basic research

Cuts to basic research funding could threaten the health of Kentucky

Written by Jay Blanton, executive director of UK Public Relations & Marketing.

Colorectal cancer incidence rates have declined by 25 percent in Kentucky in less than 10 years. Death rates have dropped by 30 percent.

Why?

Among other reasons, screenings have increased significantly, led by University of Kentucky and UK HealthCare researchers along with changes in state policy.

It’s one example of the impact that basic scientific research combined with outreach into communities can have in Kentucky. Basic scientific research is at the cornerstone of each innovation and, led by UK, it’s making a difference across Kentucky.

“Everything that we do came from a research question that was originally asked by someone either in the U.S. or internationally, so it impacts every part of our day-to-day lives,” said Lisa Cassis, UK’s vice president for research, who is nationally known and funded for her research in metabolic and obesity-associated diseases.

“Screening for colorectal cancer, for example, is a practice that most of us probably assume is routinely applied according to clinical guidelines. However, research makes a difference by asking the question: Is the screening routinely applied? And if not, then why, and how can we increase screening for this condition?” Cassis said.

Researchers at universities across the country have expressed concern over a recent proposal for next year to cut funding for biomedical research by nearly 20 percent.

U.S. Senator Mitch McConnell, the majority leader, recognizes the value of research and recently supported an increase in the budget of the National Institutes of Health by $2 billion for the remainder of this fiscal year.

McConnell and Kentucky Congressmen Andy Barr and Hal Rogers also were vocal supporters last year of the 21st Century Cures Act, which authorized federal funding increases for research on Alzheimer’s disease, cancer and opioid abuse  all issues of concern for Kentuckians. And McConnell and Barr reaffirmed their support for UK’s research efforts recently during a news conference to announce $11.2 million in federal funding to launch a new Center for Cancer and Metabolism at UK.

Nevertheless, the threat of cuts looms large and would, if enacted, hamper UK’s ability to continue to make progress in addressing the state’s health disparities, as well as threaten thousands of jobs and hundreds of millions of dollars annually in economic impact for Kentucky.

Specifically, Cassis and UK President Eli Capilouto recently cited several economic and health statistics regarding the impact in Kentucky of federal funding for basic scientific research:

  • With the proposed reduction of National Institutes of Health (NIH) funding for next year, an estimated 219 jobs at UK alone would be cut, with an effective loss of 339 jobs across the Commonwealth.
  • UK’s research enterprise has an annual economic impact of more than $580 million and more than 8,000 jobs.
  • Increasing research activity by just 15 percent means an additional nearly $90 million in economic impact and nearly 220 jobs.
  • Institutions in Kentucky earn $163.6 million ($92.4 million earned by UK) of NIH’s $26.4 billion in funding. At an estimated 13 jobs per $1 million in NIH awards, this support generates 2,886 intra/interstate jobs and has an estimated $431.6 million economic impact in Fiscal Year 2016.
  • The proposed cuts would significantly hamper UK’s ability to conduct research – and provide advanced medical healthcare – related to challenges where Kentucky is among the nation’s leaders in incidence rates for cancer, heart disease, diabetes, Alzheimer’s and death from opioid abuse. The CDC estimates hundreds of lives are lost in Kentucky’s Fifth Congressional District every year due to these largely preventable illnesses.
  • The National Institute of Food and Agriculture provides funding to 112 land-grant institutions in the U.S. to support: agriculture, food safety, agribusiness, bioenergy, 4-H, youth development and family consumer sciences.
  • One in six patents in agriculture science nationally grew from land-grant university research.
  • Six of the 10 major vaccines currently used to protect against equine infectious diseases were developed by faculty in UK’s Department of Veterinary Sciences.

Capilouto said UK’s goal with basic scientific research is to translate it as quickly as possible into treatments and solutions for communities across the Commonwealth.

“What we want to do is get the very best of our research quickly to the bedside,” Capilouto said. “We want to be able to take what we’ve learned and translate it quickly to a community to make a difference. We systematically and successfully do that at the University of Kentucky because of our capacity, our depth.”

“We can’t cut back on the pace of progress now,” Capilouto said. “Doing so threatens Kentucky’s future.”

Watch the video below to learn more about the impact basic research has on the health and wellness of Kentucky.


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