College of Graduate Studies

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Medical advances to seek blood test for determining cancer risk

DANIEL J. CRAIG | SPECIAL TO THE BLADE
PUBLISHED ON Oct. 1, 2017

Cancer is one of the deadliest human diseases and will affect almost 40 percent of men and women at some point in their lives. While each type of cancer is different, they all share one common theme: They start from a single cell and develop the ability to divide uncontrollably. Determining our risk for getting cancer is complicated because there are many factors, both inherited and environmental, that play a role.

By understanding our own genetics, it may be possible to identify people at greatest risk, allowing us to prevent or diagnose cancer early. As the rate of cancer rises around the world, wouldn’t it be useful to know if you were at greater risk based on your own genetic profile?

The human genome serves as your genetic playbook and contains about 20,000 genes composed of DNA building blocks strung together just like letters to form words. Each cell in your body activates different genes in this playbook to carry out specific functions. Throughout life, your cells are exposed to things that can cause damage to these genes, such as ultraviolet rays from the sun, environmental and household chemicals, and even natural processes associated with aging. Left uncorrected, this damage can lead to permanent changes in these genes called mutations.

Luckily, we have a variety of DNA repair and tumor prevention genes that work together to monitor the genome for damage and stop uncontrolled cell growth. Proteins produced by these genes serve as safeguards to ensure that cells with damaged DNA do not divide. Despite these protective safeguards, some DNA damage is left uncorrected, leading to mutations. While most mutations are harmless or cause a cell to die, some may occur in genes that control cell division. If a cell collects enough mutations in these critical genes, that cell may begin to divide more than normal, resulting in cancer.

Our cells may gain mutations either by inheriting them from our parents, or by collecting them throughout life.

Daniel J. Craig

The inherited mutations are present in every cell and only a few may affect risk for cancer. The mutations that we collect over time occur only in certain cells because of unrepaired DNA damage. The vast majority of human cancers are caused by a lifetime of collected mutations, which is why most cancers occur later in life.

While some inherited mutations can contribute to the risk of cancer if present in a cancer-related gene, additional mutations must also occur in a cell to overcome our genetic safeguards.

If a single cell collects multiple mutations that destroy these safeguards, that cell will divide more than it should. We recognize it as a cancer when it produces so many offspring that it interferes with the function of other cells and distorts the tissue around it.

Lung cancer is the deadliest type of cancer in the United States, killing almost 160,000 people each year — more than the next three deadliest cancers combined (breast, colon, and prostate), and about 20 percent of lung cancer cases occur in non-smokers. Early diagnosis is important because it gives doctors the chance to treat the disease when it is curable. For example, among lung cancers that are diagnosed through screening, 85 percent are in an early stage and can be cured with surgery. Without screening, the majority are in late stage and cannot be cured.

The research in our lab is focused on developing tests to diagnose cancer as early as possible and to identify people who may be at increased risk later in life because of a combination of factors.

My research focuses on developing a blood test that allows us to identify both the mutations that we inherit and those that we collect over our lifetime. Our idea is simple: If a person collects mutations at an unusually rapid rate, he or she likely does not repair DNA very well, and there is a higher likelihood of mutations in critical safeguard genes. This leads to an elevated risk for developing cancer.

This information is important because it allows us to look at inherited and environmental factors that contribute to cancer at the same time in a simple blood test. Identifying at-risk individuals before they develop cancer would allow doctors to create, and insurance companies to justify, a personalized screening plan to catch a potential cancer in its earliest stage when it is most treatable. This would not only save lives, but also save tremendously in healthcare spending.

Our research team works closely with researchers and pulmonary physicians at the University of Toledo, the Toledo Hospital, the University of Michigan, Vanderbilt University, Cleveland Clinic, the National Cancer Institute, and many other centers of excellence in lung cancer research. We are grateful for the support received from the National Institutes of Health and the George Isaac Cancer Research Fund.

Daniel J. Craig is a student studying for his PhD in the University of Toledo College of Medicine and Life Sciences Biomedical Science Program, formerly the Medical College of Ohio. Mr. Craig is doing his research in the laboratory of Dr. James C. Willey in the department of medicine. For more information, contact Daniel.Craig@rockets.utoledo.edu or go to utoledo.edu/ med/ grad/ biomedical.

 


Advances in the Study of Brain’s Link to Metabolic Syndrome

IYAD MANASERH | SPECIAL TO THE BLADE
PUBLISHED ON SEPT. 4, 2017

High blood pressure, high blood sugar, and overweight. Do these conditions scare you? Then the term “metabolic syndrome” should be a full-blown nightmare to you, because this is a combination of all these conditions within the same person. Even worse, metabolic syndrome often leads to heart disease, diabetes, and infertility.

In the United States, about 600,000 people die from heart disease every year, 26 million people have diabetes and 8 million people suffer from infertility. According to the American Diabetes Association, more than 200,000 new cases of Type 2 diabetes are diagnosed every year and many of these diabetic patients also have obesity and infertility issues. These combined illnesses have become known as the metabolic syndrome.

Insulin plays a major role in regulating both diabetes and infertility. Insulin is a molecule released by your pancreas into your blood stream when your blood sugar is high, for example, after you eat a big meal. Insulin directs the excess sugar in your blood to organs such as your liver, muscle, and fat cells to provide your body with stored energy.

We now know that more than 25 percent of men with Type 2 diabetes also have problems with infertility. Because of the increasing number of patients being treated for both infertility and diabetes, there is intense interest in developing less expensive, combined therapy for these conditions.

Iyad Manaserh is a PhD student in the department of physiology and pharmacology at the University of Toledo College of Medicine and Life Sciences Biomedical Science Program.

At the University of Toledo College of Medicine, formerly the Medical College of Ohio, our research team is focused on the brain because we believe that it is the master regulator of the metabolic syndromes.

Why the brain? What is the connection between the brain and insulin levels in your blood?

We know that specific areas in your brain control how much you eat and how your body responds to high blood sugar. Therefore, our research team is testing the idea that insulin also acts in the brain to regulate metabolic syndrome and related problems such as infertility.

Your brain has multiple regions that control diabetes, obesity, and infertility. One of these regions in the brain is called the hypothalamus, and is further divided into many important subregions. Your brain also contains two types of cells; neurons to communicate messages across the brain and glial cells, whose function has been a mystery until recently.

My research uses a mouse model to study how insulin actions in the brain affect diabetes and infertility. My first experimental step was to delete insulin receptors from specific brain glial cells called astrocytes, which become activated when insulin binds to their receptors. I wanted to know what would happen when insulin could no longer activate the astrocytes. I discovered that astrocytes without insulin receptors affect fertility, diabetes, and obesity.

My research project is to investigate insulin signaling in the brain and its effect on reproduction (fertility) and metabolism (diabetes). When I studied fertility in this mouse model, I saw a delay in onset of puberty in the sick mouse model without insulin receptors, when compared to control healthy mice. Also, the sick female mice did not have regular menstrual cycles. I also observed a reduction in brain fertility hormone levels as well as ovary and testis hormone levels in the sick mice. I also found that pregnancy rate for the sick female mouse model was reduced dramatically when compared to that of healthy mice. I found similar results of decreased fertility in the sick male mouse model when compared to healthy mice. All of these findings indicate that insulin activity in brain cells affects fertility in important ways.

When I studied diabetes and obesity in this mouse model, as we had suspected, there were profound effects. The sick mouse model showed an increase in body weight from the first month and become outright obese by 6 months of age (equal to a 35-40 year old human).

This was the first hint that the sick mouse model would eventually become diabetic. Indeed, the sick mouse model is also prediabetic at an early age and becomes diabetic by 6 months of age. I also checked overall fat and muscle content in the sick mouse model and, as expected, I measured increased fat and low muscle content, also confirming obesity in the sick mouse model.

These combined findings indicate that insulin in the brain is critical in treating obesity, diabetes, and infertility. We are planning to use these results to help identify new drugs that will target these conditions simultaneously thereby lowering the cost of using of multiple drugs.

Iyad Manaserh is a PhD student in the department of physiology and pharmacology at the University of Toledo College of Medicine and Life Sciences Biomedical Science Program. Mr. Iyad is doing his research in the laboratory of Jennifer Hill. For more information, contact Iyad.Manaserh@rockets.utoledo.edu.


New Teaching Assistant Training – August 24, 2017

Attention new Fall 2017 Teaching Assistants. For detailed agenda, please Click Here.


BIG FISH: Jessica Sherman Collier, grad student, Finalist for National Fellowship Sea Grant [VIDEO]

A University of Toledo graduate student in biology who has been working to restore giant, ancient sturgeon to Lake Erie was recently selected as one of 61 finalists across the country by Sea Grant for the 2018 Knauss Fellowship.

As a finalist, Jessica Sherman Collier, PhD student researcher in UT’s Department of Environmental Sciences, will spend a year working in Washington, D.C., on water resource policy.

“I am very excited and quite honored to be selected for this fellowship,” said Sherman Collier, who was recommended to Sea Grant by her PhD adviser Dr. Jonathan Bossenbroek. “The Knauss Fellowship is an amazing opportunity, and I am so happy to represent The University of Toledo and the Great Lakes region while I am there.”

Sherman Collier will spend a week in November interviewing with up to 20 different federal agency and legislative offices, such as the National Oceanic and Atmospheric Administration, Department of Interior, National Science Foundation, U.S. Navy, and the Senate Committee on Commerce, Science and Transportation. After being matched with her fellowship placement, her work will begin in February.

“This is a great launch to Jessica’s career, and I hope she finds satisfaction doing work as a public servant for the betterment of our environment,” said Dr. Tim Fisher, geology professor, chair of the UT Department of Environmental Sciences, and interim director of the Lake Erie Center.

“We are excited about the talent and perspectives the 2018 Knauss Fellowship finalists will bring to their executive and legislative appointments next year,” Jonathan Pennock, director of the National Sea Grant College Program, said. “The Knauss Fellowship is a special program for Sea Grant, and we are proud of the professional development and opportunities Sea Grant has provided our alumni, the current class and now these finalists.”

Knauss finalists are chosen through a competitive process that includes several rounds of review.

Since 1979, Sea Grant has provided more than 1,200 early-career professionals with firsthand experiences transferring science to policy and management through one-year appointments with federal government offices in Washington, D.C.

Sherman Collier, who also is president of the North American Sturgeon and Paddlefish Society Student Subunit, has been involved in the project to restore lake sturgeon to Lake Erie. Most recently, she helped the Toledo Zoo secure $90,000 in federal grant money to build a sturgeon rearing facility along the Maumee River, which flows into Lake Erie. Sherman Collier assisted the project by verifying that spawning and nursery habitat still ex

ist in the Maumee River to sustain a population of the fish that can live to be 150 years old and grow up to 300 pounds and eight feet long.

“I have enjoyed working with partners at the zoo, as well as state and federal agencies to give these large and ancient fish a chance to thrive in Lake Erie once again,” Sherman Collier said. “This is an instance when scientists and natural resource managers have the opportunity to improve the state of an ecosystem by restoring a species that belongs there and to learn a good lesson about our actions in the past.”

BIG FISH:  Jessica Sherman Collier, grad student Finalist for national fellowship Sea grant


Thomas Lai, graduate student, awarded Spitzer Fellowship in astronomy

“As a teenager, gazing at the stars on the dark canvas of the sky was like entering the most luxurious cinema,” reminisced Thomas Lai, a graduate student studying astronomy. “Soon I picked up the habit of staying in the dark whenever I could, and to recognize as many constellations as possible during my high school years.

“In retrospect, I can see this as a sparkle of the beginning of my interest in the enigmatic cosmos.”

Lai’s passion and hard work were recognized by the Department of Physics and Astronomy: He recently received the Doreen and Lyman Spitzer Graduate Fellowship.
The fellowship is named after Toledo natives. Lyman Spitzer was a world-renowned physicist and astronomer, who was an early proponent of a project that became the Hubble Space Telescope. The Spitzer Space Telescope, launched in 2003, is named after the scientist. Doreen Spitzer was a prominent archaeologist who had an affinity for all things Greek.

Lai, with assistance from Dr. Adolf Witt, Distinguished University Professor Emeritus of Astronomy, and Dr. JD Smith, associate professor of astronomy, was able to publish a study on light emissions from nebulae in the Cassiopeia constellation.

“I was extremely pleased that we were able to offer the Spitzer Fellowship to Thomas. He was clearly qualified; he was eager to start an independent research project during his first year as a graduate student at UT, which the Spitzer Fellowship made possible,” Witt said. “The data for this project had been secured beforehand by my collaborator, Ken Crawford, and myself. This allowed Thomas to enter right at the data calibration, reduction and analysis stage of the project — the phase where scientific results and conclusions are being extracted from a collection of images and numbers.

“I enjoyed working with Thomas. The fact that the project resulted in a peer-reviewed scientific paper in a major journal within about two years speaks for itself.”

“They showed me not only the method in conducting research, but also the right attitude in finding the reasonable answer,” said Lai, regarding the aid he received from Witt and Smith.

On the results of his study, Lai said, “I am particularly interested in extended red emission, because we understood little about the exact emission process and the carrier involved in producing such light, even though it has been studied for more than 40 years. To summarize this study, we attributed the extended red emission to a fluorescent process, namely the recurrent fluorescence, which enables small and fragile particles in interstellar space to dissipate their energy efficiently after being bombarded by high-energy photons originating in an illuminating star. This mechanism prevents particles from getting destroyed in the harsh environment filled with ultraviolet radiation from stars, and it may be a crucial process for increasing the survival rate of small carbonaceous molecules, which might be the building blocks of life.”

Though great progress has been made, Witt pointed out the work of a scientist is never finished: “It is an important part of the research experience that every successfully completed project should lead to new questions, which then demand follow-up studies. This has been the case with our work as well. A new question has emerged from some of our current findings, the solution to which we are pursuing through observations with the 4.3-meter Discovery Channel Telescope in Arizona and the 10-meter Keck II telescope on Mauna Kea, Hawaii. This will most likely be part of Thomas’s PhD thesis.”

Luckily, Lai’s passion for this field will surely lead to many more years of scientific discovery.

“Having this paper published means a lot to my career in astronomy,” Lai said. “It encourages me to find more intriguing phenomena provided by the universe and to reveal those profound facts hidden by wonders of the nature.”