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Circadian clock research may enable flexible designer plants; treat cancer and diabetes

Understanding of photoreceptor proteins could lead to new strains of plants tolerant to greater variety of environments, and to cancer drug therapy for humans

How does a plant know when to sprout a leaf, fold its petals or bloom? Why do humans experience jet lag after a trip abroad?

The answer is the internal circadian clocks that are present in nearly every organism and that respond to external cues such as light and temperature, says chemist Brian D. Zoltowski, Southern Methodist University.

Zoltowski’s lab at SMU studies one of the many proteins involved in an organism’s circadian clocks. Called a photoreceptor, the protein responds to light to predict time of day and season by measuring day length.

$250,000 grant will fund research studying circadian clocks in plants
The photoreceptor protein enables plants to know when spring and fall occur and to produce flowers or fruit at the appropriate time of year, says Zoltowski, an assistant professor in SMU’s Department of Chemistry. The protein also allows plants to collect energy during the day in the scientific process called photosynthesis, and then refocus energy to grow at night.

Human photoreceptors also are intricately involved in regulation of the body’s circadian clocks. They have been implicated in the development of cancer and diabetes, as well as neurological illnesses.

“If we can better understand how these proteins work, we can potentially re-engineer them or develop small molecules to regulate flowering times, plant growth and development,” Zoltowski says. “By extension, we can potentially design therapeutics for the human circadian clocks.”

The Herman Frasch Foundation for Chemical Research Grants in Agricultural Chemistry awarded Zoltowski a five-year $250,000 agricultural chemistry grant to fund the plant research. The foundation is part of the American Chemical Society.

A natural 24-hour biological mechanism for regulating the body
The circadian clock is an internal biological mechanism that responds to light, darkness and temperature in a natural 24-hour biological cycle. The clock synchronizes body systems with the environment to regulate everything from sleep patterns and hunger in humans to growth patterns and flowering in plants.

“Our research focuses on understanding the chemical basis for how organisms perceive their surroundings and use light as an environmental cue to regulate growth and development,” Zoltowski says.

Zoltowski’s research focuses on a family of proteins related to Zeitlupe, a photoreceptor protein that is sensitive to blue light and historically considered responsible for regulating the circadian clock.

Light induces chemical reaction and resulting cascade of interactions
“We isolate the protein so we can study directly how it works independent of everything else,” Zoltowski says. “So we look at the chemistry that is sensitive to blue light when the blue-light photon is absorbed by the protein. We figure out the chemistry and then how the chemistry changes the structure of the protein.”

For example, he says, for a flower to open, light induces a chemical reaction in the protein that alters the way it’s configured, which then starts a cascade of interactions that changes the plant’s physiology completely.

The researchers use a combination of X-ray crystallography, nuclear magnetic resonance and solution biophysics to identify the fundamental chemical mechanisms of photo-activation, including local chemical events, alteration in protein structure and alteration in protein:protein interactions.

Goal is for discoveries that can regulate a plant’s circadian clock
By understanding how the proteins work, scientists can ultimately create new strains of plants that are tolerant to more environments, says Zoltowski. In related research, the study of human proteins can reveal circadian clock irregularities that play a role in diseases such as diabetes by disrupting the release of glucose, for example. From that research, scientists can develop new drug therapeutics to treat the illness.

“We’re having great success. We’ve worked with these families of proteins for a long time, so we have some strategies that improve the likelihood of making it work,” Zoltowski says. — Margaret Allen

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Health & Medicine Researcher news SMU In The News

CBS DFW: Is Aerial Spraying Safe?

CBS Channel 11 reporter Ginger Allen interviewed SMU chemist Brian Zoltowski for the station’s Aug. 15 report on aerial spraying over Dallas County to kill mosquitos that may be carrying West Nile Virus.

The report comes in the wake of a decision by Dallas County to address the spread of West Nile Virus with aerial spraying of a pesticide called Duet.

Zoltowski, an SMU assistant professor of chemistry, was asked about the possible impact of the pesticide on human health.

See the full report.

EXCERPT:

Reporting: Ginger Allen
CBS Channel 11 DFW

DALLAS (CBS 11 NEWS) – West Nile poses a serious health risk, but now with aerial spraying, there is a new concern. What could soon rain down over Dallas County may flood doctors’ offices with questions.

Doctor Elizabeth Stevenson is an OB/GYN who says, “Unfortunately, right now, we don’t have a whole lot of information.”

Although Doctor Stevenson has delivered more than 4,000 babies, she, like the rest of us, is waiting to hear what the chemicals that kill mosquitoes could do to at risk patients like infants and pregnant women.

“We are going under the assumption that this will not be harmful to mother or unborn child,” says Doctor Stevenson.

CBS 11 has learned Dallas County will be using Clarke, an Illinois company to spray the pesticide called Duet. Duet contains sumithrin and pralletrin.

“If you ever take Raid and spray on a bug, they basically drop to the ground. That is what they are designed to do. They basically stop their ability to move,” explains Southern Methodist University Associate Professor Brian Zoltowski.

Zoltowski says these are chemicals that the pest control companies have being spraying on yards for years. He says the amounts that will be sprayed will kill mosquitoes, bees and fish. They do not have the protective enzymes to degrade the molecules that people and pets do. […]

See the full report.

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Researcher news SMU In The News Technology

Science Daily: Scientists Find Simple Way to Produce Graphene

The online science news site Science Daily has covered the research of SMU Chemistry Department Professor John A. Maguire.

The June 21 article “Scientists Find Simple Way to Produce Graphene” reports the news that Maguire and a team lead by scientists from Northern Illinois University have discovered a simple method for producing high yields of graphene, a highly touted carbon nanostructure that some believe could replace silicon as the technological fabric of the future.

Read the full story.

Excerpt:

By Science DailyScientists at Northern Illinois University say they have discovered a simple method for producing high yields of graphene, a highly touted carbon nanostructure that some believe could replace silicon as the technological fabric of the future.

The focus of intense scientific research in recent years, graphene is a two-dimensional material, composed of a single layer of carbon atoms arranged in a hexagonal lattice. It is the strongest material ever measured and has other remarkable qualities, including high electron mobility, a property that elevates its potential for use in high-speed nano-scale devices of the future.

In a June communication to the Journal of Materials Chemistry, the NIU researchers report on a new method that converts carbon dioxide directly into few-layer graphene (less than 10 atoms in thickness) by burning pure magnesium metal in dry ice.

“It is scientifically proven that burning magnesium metal in carbon dioxide produces carbon, but the formation of this carbon with few-layer graphene as the major product has neither been identified nor proven as such until our current report,” said Narayan Hosmane, a professor of chemistry and biochemistry who leads the NIU research group.

Read the full story.

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Health & Medicine Mind & Brain Researcher news SMU In The News

Dallas Business Journal: Firm is out to prevent neuron loss

Investigators at SMU and the University of Texas at Dallas have discovered a family of small molecules that shows promise in protecting brain cells against nerve-degenerative diseases such as Parkinson’s, Alzheimer’s and Huntington’s. SMU’s work is led by Chemistry Department Professor Edward R. Biehl.

Health care journalist Bill Hethcock covered the research for The Dallas Business Journal. Hethcock’s Feb. 25 article “Firm is out to prevent neuron loss” details how Dallas-based startup EncephRx Inc. was granted worldwide license to develop the jointly owned compounds.

EXCERPT:

By Bill Hethcock
Dallas Business Journal

Dallas-based biotech startup EncephRx Inc. is working with researchers at the University of Texas at Dallas and Southern Methodist University to develop treatments for Huntington’s, Parkinson’s and Alzheimer’s diseases. Already, there have been signs of promise in animal testing. The company is seeking $1 million in grants and private equity to begin pre-clinical testing in the next year.

The goal is to develop and commercialize treatments that prevent the progressive loss of neurons that characterize the diseases, said Aaron Heifetz, CEO of EncephRx. Available medications attempt to relieve symptoms, but don’t prevent neuron loss and disease progression, he said.

DBJ subscribers can read the full story

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Culture, Society & Family Health & Medicine Mind & Brain

Novel compounds show early promise in treatment of Parkinson’s, Huntington’s, Alzheimer’s

Success with human trials could lead to new drugs to halt progression of nerve-degenerative diseases

Investigators at Southern Methodist University and The University of Texas at Dallas have discovered a family of small molecules that shows promise in protecting brain cells against nerve-degenerative diseases such as Parkinson’s, Alzheimer’s and Huntington’s, which afflict millions.

Dallas-based startup EncephRx, Inc. was granted the worldwide license to the jointly owned compounds. A biotechnology and therapeutics company, EncephRx will develop drug therapies based on the new class of compounds as a pharmaceutical for preventing nerve-cell damage, delaying onset of degenerative nerve disease and improving symptoms.

Treatments currently in use don’t stop or reverse degenerative nerve diseases, but instead only alleviate symptoms, sometimes with severe side effects. If proved effective and nontoxic in humans, EncephRx’s small-molecule pharmaceuticals would be the first therapeutic tools able to stop affected brain cells from dying.

“Our compounds protect against neurodegeneration in mice,” said synthetic organic chemist Edward R. Biehl, the SMU Department of Chemistry professor who led development of the compounds at SMU. “Given successful development of the compounds into drug therapies, they would serve as an effective treatment for patients with degenerative brain diseases.”

EncephRx initially will focus its development and testing efforts toward Huntington’s disease and potentially will have medications ready for human trials in two years, said Aaron Heifetz, CEO at EncephRx.

Compounds developed by SMU and UTD collaboration
Biehl developed the compounds in collaboration with UT Dallas biology professor Santosh R. D’Mello, whose laboratory has been studying the process of neurodegeneration for several years.

“Additional research needs to be done, but these compounds have the potential for stopping or slowing the relentless loss of brain cells in diseases such as Alzheimer’s and Parkinson’s,” said D’Mello, professor of molecular and cell biology at UT Dallas, with a joint appointment in the School of Brain and Behavioral Science. “The protective effect that they display in tissue culture and animal models of neurodegenerative disease provides strong evidence of their promise as drugs to treat neurodegenerative disorders.”

Millions are suffering, particularly the elderly
Parkinson’s, Huntington’s and Alzheimer’s are disorders of the central nervous system marked by abnormal and excessive loss of neurons in a part of the mid-brain, say the researchers.

The diseases steadily erode motor skills, including speech and the ability to walk, cause tremors, slowed movement, stooped posture, memory loss and mood and behavior problems.

The risk of developing a degenerative nerve disease increases with age. These diseases affect more than 5 million Americans.

Novel compounds effectively proved protective in initial studies
One member of a class of heterocyclic organic compounds, the synthetic chemicals developed and tested by SMU and UT Dallas scientists, was shown to be highly protective of neurons in tissue culture models and effective against neurodegeneration in animal models.

The most promising lead compound, designated HSB-13, was tested in Huntington’s disease animal models. It not only reduced degeneration in a part of the forebrain but also improved behavioral performance while proving nontoxic. The compound also was efficacious in a commonly used fly model of Alzheimer’s disease.

“These preliminary tests demonstrated that the compound was an extremely potent neuroprotective agent,” Biehl said.

The findings were published in the article “Identification of novel 1,4-benzoxazine compounds that are protective in tissue culture and in vivo models of neurodegeneration,” which appeared in the Journal of Neuroscience Research. The National Institutes of Health and the Defense Advanced Research Projects Agency funded the project.

The SMU and UT Dallas researchers developed and tested more than 100 compounds for neuroprotective efficacy and toxicity over the course of four years before making the discovery in 2007.

Interinstitutional partnership with EncephRx
SMU researchers will assist EncephRx in optimizing the primary compound, and the UT Dallas team will support testing and analysis.

“While discovery of the compounds is a major accomplishment, many hurdles remain,” Biehl said.

EncephRx is a university spinout formed to develop and commercialize the compounds. Its management team has proven success in all facets of drug development and has developed more than a dozen chemical compounds.

Aaron Heifetz, president and chief executive officer of EncephRx, Inc., said, “We believe this library of novel neuroprotective compounds will prove an important step in the effort to improve the health for patients with neurodegenerative diseases, such as Huntington’s disease, Alzheimer’s disease and Parkinson’s disease.”

Chris Jeffers, managing partner of FirstStage Bioventures, the parent company of EncephRx, added, “FirstStage is very excited about this technology and looks forward to helping EncephRx quickly move these compounds into the clinic.”

SMU has an uplink facility on campus for live TV, radio or online interviews. To speak with Dr. Biehl or Dr. D’Mello or to book them in the SMU studio, call SMU News & Communications at 214-768-7650 or UT Dallas Office of Media Relations at 972-883-4321.

SMU is a private university in Dallas where nearly 11,000 students benefit from the national opportunities and international reach of SMU’s seven degree-granting schools. For more information see www.smu.edu.