College of Graduate Studies

Author Archive

Youjie Zhang, Ph.D student, study on exercise, genes, and bacteria connection | Special to The Blade

| SPECIAL TO THE BLADE
PUBLISHED ON April 1, 2018

Exercise is a natural activity that helps our bodies stay healthy and function well. Lack of exercise is a major cause of obesity, diabetes, and heart diseases.

Today, many of us do not get enough exercise and we eat too much, increasing our chances of being diagnosed with these diseases.

Exercise can be prescribed by your doctor, along with drugs for treating many diseases such as heart disease. However, people with low-exercise capacity are limited in the amount of exercise they are able to do. Scientific measurements can be done in the clinic to determine your capacity for exercise, which is controlled by your inherited genetics and your environment. Your environment can be changed, but your genetic inheritance cannot.

Youjie Zhang is a Ph.D. student in the Molecular Medicine track in the Department of Physiology and Pharmacology in the University of Toledo College of Medicine and Life Sciences Biomedical Science Program.

Our research challenge at the University of Toledo College of Medicine and Life Sciences is to understand how your genetic makeup contributes to your exercise capacity. I am training in the laboratory of Dr. Bina Joe, one of the leading laboratories in this field. One of our experimental systems is inbred animal models, raised in the same environment, with similar genetic makeups, to study the genetics of disease. Our research team has successfully developed two inbred rat models of exercise capacity: low-capacity runners and high-capacity runners.

We can measure exercise capacity by measuring the maximum amount of oxygen that you are able to use during hard exercising, such as running on a treadmill. We found that our rat models of high-capacity runners have significantly higher oxygen use than the low-capacity runners. In addition, similar to humans, the low-capacity runners can’t use as much oxygen and develop many diseases including obesity, high blood pressure, heart disease, depression-like behavior, and decreased memory.

We have now identified millions of genetic differences between low-capacity runners and high-capacity runners’ DNA sequences. The high-capacity runners have inherited genes in their DNA which promote both their willingness and ability to exercise. The low-capacity runners have inherited genes which do not promote their ability to exercise but promote their willingness to be couch potatoes.

These observations provide evidence for the existence of good and bad genes which can be inherited and can function to prevent or promote disease, respectively. But we still don’t understand what these good and bad genes are or how they function to prevent or promote disease.

One surprising, but important clue came from our observation that the low-capacity runners and high-capacity runners had profound differences in their gut microbiota. Gut microbiota are the tiny bacteria that live in our intestine. There are tens of trillions of bacteria in our gut, which include more than 1,000 different types of bacteria. These bacteria are now well recognized as an important factor contributing to diseases such as obesity, hypertension, and depression.

We have found that the high-capacity runners accumulate different types of bacteria in their guts compared to the low-capacity runners. For example, a group of bacteria called Actinobacteria was significantly higher in low-capacity runners compared with high-capacity runners. We then found that Actinobacteria was negatively associated with exercise capacity, and positively associated with increased body fat and depression.

Further research is underway to obtain more detailed information, with the goal of identifying all of the good and bad genes of the low-capacity runners and high-capacity runners. This evidence of interaction between your genes and your gut bacteria suggests that control of gut bacteria might be a novel therapeutic approach for the treatment of low exercise capacity or diseases due to low exercise capacity.

Youjie Zhang is a PhD student in the Molecular Medicine track in the Department of Physiology and Pharmacology in the University of Toledo College of Medicine and Life Sciences Biomedical Science Program. His research is supported by a grant from the National Institutes of Health to Dr. Bina Joe. For more information, contact Youjie.Zhang@rockets.utoledo.edu or go to utoledo.edu/med/grad/biomedical.


The Tony Quinn We Are STEMM Fellowship Fund Ensuring ongoing support of underrepresented graduate students in STEMM disciplines

UT News
PUBLISHED ON MAR. 12, 2018

The new Tony Quinn We Are STEMM Initiative recognizes the immunologist in the Department of Biological Sciences for his work in deciphering the interplay between diabetes and immunity, as well as his dedication to the recruitment and retention of underrepresented minority students.

Dr. Anthony Quinn, associate professor of biological sciences and assistant dean for diversity and inclusion in the College of Natural Sciences and Mathematics, created in 2015 a We Are STEMM initiative designed to bring high-profile underrepresented minority scientists to UT in the fields of science, technology, engineering, mathematics and medicine as role models for University students of color, inspiring them to engage in STEMM fields of study.

In recognition of his contributions during his 16 years of educational leadership, UT has created the Tony Quinn We Are STEMM Initiative that will build upon the existing We Are STEMM lecture series to also include fellowships for graduate and professional education and mentoring programs.

“Tony’s dedication and contributions of energy and intellect to the full participation of individuals from marginalized groups in the scientific enterprise has benefited The University of Toledo and our community greatly,” said Dr. Amanda Bryant-Friedrich, dean of the College of Graduate Studies. “His work has impacted our students at all levels through the creation of a diverse and inclusive campus. This work must continue.”

While battling pancreatic cancer, Quinn co-developed UT’s strategic plan, co-directed the Multicultural Emerging Scholars Summer Bridge and Living Learning Community Program, and led the Brothers on the Rise mentoring program.

“We recently visited Dr. Quinn and his family where we shared with them this recognition. They are pleased to have this honor in recognition of Tony’s contribution to the University,” said Dr. Willie McKether, vice president for diversity and inclusion.

The Tony Quinn We Are STEMM Fellowship Fund has been created to support the initiative to ensure ongoing support of underrepresented graduate students in STEMM disciplines — scholars so important to Quinn.

For more information about donating to the fund, visit utfoundation.org/give/quinnfellowship.


Sandum Kalpana, Ph.D. student, investigates ways to reduce metastasis of breast cancer cells l Special to The Blade

SANDUM KALPANA | SPECIAL TO THE BLADE
PUBLISHED ON MAR. 4, 2018

Cancer is a deadly disease that destroys human health and well-being. In 2017, there were more than a million new cancers diagnosed and more than 600,000 cancer deaths in the United States.

More than half of these cancer deaths were because of secondary tumors, called metastases that grow in a completely separate part of the body than the primary tumor. Metastases are deadly when they grow in vital organs such as the brain or lung.

The process of tumor metastasis can be compared to how nature sends plant seeds to distant geographic sites, using different methods of transportation.

Sandun Kalpana is studying for her PhD at the University of Toledo College of Medicine and Life Sciences Biomedical Science Program.

Tumor seeding and growth in a new location is a complicated process. To begin this process, a single tumor cell must detach from the primary tumor and travel through the surrounding tissue, toward a major circulatory system in the body, such as the blood. Then this cell has to get through a protective wall and enter the bloodstream to travel to a new site in the body. During its ride, this tumor cell must hide from millions of immune cells trained to kill any foreign cells in the blood. If the tumor cell survives this trip, it will then leave the bloodstream at a distant tissue and attempt to grow there. This whole process is very challenging, therefore only about one in ten thousand tumor cells that enter the bloodstream can successfully travel to a new location and start a secondary tumor.

Which cells in the primary tumor decide to take this dangerous trip, and which cells decide not to travel? We are investigating this question by looking closely at specific cellular activities during metastasis. I am part of a research team in Kam Yeung’s lab in the Department of Cancer Biology at the University of Toledo College of Medicine and Life Sciences, formerly the Medical College of Ohio. We are investigating a small cellular protein, called Raf-1 kinase inhibitor protein or RKIP, which suppresses metastasis when it is activated.

We are one of the leading laboratories in the RKIP research field. Several independent studies, including ours, have shown that RKIP suppresses metastasis in different tumor types, such as prostate cancer, melanoma, breast cancer, and colon cancer. This is because RKIP controls several other important proteins in the cell. When the expression of RKIP is turned off in tumor cells, these other proteins behave without control, giving these tumor cells a metastatic travel permit.

Our research team understands that the uninhibited RKIP-binding proteins are just the first step in a cellular signaling pathway to allow a tumor cell to metastasize. We are trying to identify other proteins that are controlled by these RKIP-binding proteins when RKIP is turned off. One potential cellular protein we discovered in a breast cancer cell model is called RhoA.

We know that when RKIP is turned on in breast cancer cells, RhoA is more active. When RhoA is active, it stabilizes another protein that helps keep cells attached to each other. So when there is more RhoA activity in tumor cells, they keep attached to other tumor cells and cannot metastasize. When RKIP is turned off in tumor cells, they have less active RhoA, which decreases cell-cell attachments, giving these cells a metastatic travel permit.

We are investigating the detailed mechanisms of relationships between RKIP, RhoA, and cell attachment proteins in metastatic breast cancer cells. We are also using a breast cancer mouse model to confirm our preliminary findings in the cell culture model. Our ultimate goal is to identify proteins that are regulated by RKIP-binding proteins and target these for therapy to reduce metastasis of breast cancer cells.

Sandun Kalpana is a student earning her PhD in the University of Toledo College of Medicine and Life Sciences Biomedical Science Program. She is doing her research in the laboratory of Kam Yeung, PhD, in the Department of Cancer Biology. For more information, contact Gardiyawasam.Kalpana@rockets.utoledo.edu or go to utoledo.edu/ med/ grad/ biomedical.


Hilda Ghadieh, Ph.D student, examines treatment for liver disease | Special to The Blade

HILDA GHADIEH | SPECIAL TO THE BLADE
PUBLISHED ON Feb. 4, 2018

Metabolic syndrome is a group of medical conditions associated with obesity.They are a cluster of abnormalities that include extra fat deposited in the abdominal area, blood vessels, and liver.

Extra fat in the liver that is not caused by alcohol is called nonalcoholic fatty liver disease. There are two types of nonalcoholic fatty liver disease; one type is a simple fatty liver called nonalcoholic fatty liver and the other is nonalcoholic steatohepatitis.

The livers of patients with nonalcoholic steatohepatitis become inflamed in addition to the extra fat. When a fatty liver has chronic inflammation, it eventually forms scar tissue to replace dead liver cells, called fibrosis. If untreated, this condition will eventually develop into cirrhosis leading to liver failure. Liver failure requires transplantation of a new liver for the patiend to survive. Sometimes liver cancer will develop instead.

Hilda Ghadieh is a PhD graduate student at the University of Toledo College of Medicine and Life Sciences Biomedical Science Program.

Nonalcoholic steatohepatitis is reaching epidemic numbers around the globe, especially among obese people. Millions of Americans have this condition. This is a silent process that doesn’t cause symptoms, and there is no laboratory test to detect it except for a liver biopsy.

Developing a drug for nonalcoholic steatohepatitis is very challenging because it is a very complex condition and we have limited understanding of how the disease develops and/or progresses. Moreover, there is no animal model that replicates all features of human nonalcoholic steatohepatitis, therefore searching for effective drugs is difficult. Thus, it is important for us to generate proper animal models to help understand this disease and test for the best treatments.

The most successful drugs are the ones that can target the three components of nonalcoholic steatohepatitis, fatty liver causing inflammation, which then turns into liver fibrosis.

I am training in the laboratory of Sonia Najjar to study this complex disease, because this is one of the leading laboratories in this field of research. One of the research projects in our laboratory has been to test current drugs to develop a safe and effective medicine for long term use in patients with nonalcoholic steatohepatitis.

Insulin resistance also leads to nonalcoholic fatty liver disease. Restoring insulin sensitivity is very important in this group of patients to maintain correct sugar levels in the blood. Insulin action is determined by how much is released from your pancreas and how much is removed by your liver.

You can think of normal insulin levels as the heat in your home that controls your thermostat. Too much heat and the thermostat turns off, not enough heat and the thermostat turns on, similar to plasma insulin levels regulating its own action. However, if you have a chronically abnormal increase in blood insulin levels, this will eventually lead to insulin resistance because cells in your body stop responding to insulin.

My investigations focus on a protein called CarcinoEmbryonic Antigen-related Cell Adhesion Molecule 1 (CEACAM1). This protein is highly expressed in your liver and it plays a major role in removing insulin from your bloodstream. We have found that patients with fatty liver, insulin resistance, and obesity have marked reduction in CEACAM1 protein levels.

We have a mouse model that does not express CEACAM1 in any organ. When fed a regular diet, this mouse model has extra fat in the liver, along with inflammation and fibrosis. Importantly, when fed a high-fat diet, this mouse model develops all of the key features of human nonalcoholic steatohepatitis. Having a mouse model deficient in CEACAM1 is a very good tool to study fatty liver disease and to investigate commercially available drugs for treatment.

First on our list of drugs to investigate was exenatide, a drug that is used to treat patients with type 2 diabetes (adult onset) by causing insulin release from the pancreas. Exenatide helps to maintain insulin sensitivity and thus corrects sugar levels in these patients.

We wanted to know if exenatide can promote insulin removal from the blood by increasing CEACAM1 expression in the liver. We also wanted to know if this method of controlling insulin levels could reverse fatty liver, inflammation and fibrosis.

To answer these questions, we first put normal mice and others lacking CEACAM1 expression on high fat diet for a month to make them obese. Then we treated them with exenatide during the second month of their high fat diet. We observed that exenatide was able to increase CEACAM1 expression in the liver, restoring the metabolic diseases that were because of high fat intake in normal mice but not in the mice lacking CEACAM1.

Thus, exenatide maintains normal blood insulin level by increasing CEACAM1 expression in the liver. In other words, insulin release from the pancreas and clearance by the liver should go hand in hand to maintain insulin sensitivity. Moreover, the increase in CEACAM1 expression also restored fat accumulation, inflammation and fibrosis in the livers of normal mice.

Collectively, these data indicate the importance of CEACAM1 as a promising therapeutic target in liver cells for the prevention and/or treatment of nonalcoholic steatohepatitis.It is our hope to develop a novel drug against nonalcoholic steatohepatitis that induces CEACAM1 expression to limit fat accumulation in the liver.

Hilda Ghadieh is a PhD graduate student at the University of Toledo College of Medicine and Life Sciences Biomedical Science Program. She is completing her doctoral studies in the molecular medicine track in the lab of Sonia Najjar, John J. Kopchick PhD fellow, endowed eminent research chair, professor of department of biomedical sciences, Heritage College of Osteopathic Medicine, Ohio University. For details email Hilda.Ghadieh@rockets.utoledo.edu or go to utoledo.edu/​med/​grad/​biomedical.


Lesley Li, Ph.D. student, investigates how cells communicate | Special to The Blade

ZEHUI (LESLEY) LI | SPECIAL TO THE BLADE
PUBLISHED ON Dec. 31, 2017

Cells are the basic structural units that are used to build all of the organs in your body. A surface membrane surrounds each cell, just like your skin surrounds you. The cell membrane controls the entry and exit of different things, including food and specific molecules that can change the rate of cell growth and division.

One way that the cell membrane can bring in other molecules is within small bubble-like structures that pinch off and move inside the cell. Such bubbles are called endosomes (inside cell).

Zehui (Lesley) Li, a student at the University of Toledo, is studying chemical messengers between cells and how they can potentially be used to treat cancer.

Once inside the cell, each endosome can make even smaller bubbles within it. These smaller bubbles are called intraluminal vesicles (ILVs). These ILVs are so small that they can only be seen using a very high-powered microscope.

Scientists have now discovered that endosomes can return to the cell surface, where they fuse back with the cell membrane and release small ILV bubbles outside the cell. Once they leave the cell, the tiny bubbles are called exosomes (outside cell).

These exosomes float in your body fluid and eventually attach to other cell membranes and enter the new cell. After they move in, molecules inside of the bubbles will be released into the new cell to affect cell growth and other cell activities.

These tiny exosomes represent an important way for cells to communicate and influence each other, because they often carry signaling molecules and other materiel (good or bad) from their original cell.

However, there is still much we do not understand about these communicating exosomes, such as how their production is controlled, which cells they specifically communicate with, and how many different types of communication they use.

Our research laboratory is very interested in this important method of cell communication specifically between cancer cells. Both normal cells and cancer cells can release exosomes, which can be found in different body fluids, such as blood, urine, and saliva. The liquid medium used to grow cells in culture dishes in the laboratory also contains exosomes released from the growing cells.

There is now a great deal of interest within the scientific community in the molecular content of exosomes released from cancer cells, because they might contain different molecules that send different messages, compared to exosomes released from normal cells. Such information could be used to detect the presence of cancer or to monitor the response of cancer cells to therapy.

An additional exciting investigation is to use these tiny exosomes as carriers for drugs to treat cancer and other diseases. One of the major technical hurdles is how to make cells in culture produce exosomes in large amounts.

Researches found that cells treated with a unique chemical produced many more exosomes.

Our research laboratory at the University of Toledo College of Medicine and Life Sciences, the former Medical College of Ohio, has been investigating new drugs to treat brain tumors. We became very interested in the exosome investigations after we began studies with a unique chemical, abbreviated MOPIPP. We discovered that MOPIPP causes balloon-like structures, similar to endosomes, within brain tumor cells.

We then wondered whether these endosomal structures could also produce exosomes. To answer this question, we treated human brain tumor cells in culture with MOPIPP and then used specialized methods to analyze exosomes from the liquid medium surrounding the cells.

We found that the exosomes and their contents that we collected from the MOPIPP-treated cells were similar to exosomes collected from untreated cells. But, to our surprise, the cells treated with MOPIPP released three to five times more exosomes than the untreated cells.

Most importantly, the cells treated with MOPIPP continued to grow normally, suggesting that, except for the larger bubbles and increased exosome production, MOPIPP did not have any lasting ill effects on the cells.

We now plan to investigate the exact mechanism that leads to the large boost in exosome production after MOPIPP treatment. These exciting preliminary results indicate that MOPIPP and similar chemicals could be useful as novel tools to produce exosomes in large-scale for cancer therapy.

Zehui (Lesley) Li is a student earning her PhD in the University of Toledo College of Medicine and Life Sciences Biomedical Science Program. Lesley is doing her research in the laboratory of William Maltese, PhD, in the Department of Cancer Biology. For more information, contact Zehui.Li@rockets.utoledo.edu or go to utoledo.edu/ med/ grad/ biomedical.


UT Astronomy Program Launched to a New Level

CHERIE SPINO | UT News
PUBLISHED ON Dec. 6, 2017

The University of Toledo’s partnership with the Discovery Channel Telescope in Arizona has helped launch the UT astronomy program onto a new level. For the first time, a UT graduate student published a significant paper made possible by data collected from observations with the telescope.

The paper on the properties of interstellar dust appears as a cover feature article in the September issue of Astronomy & Astrophysics. The UT research team studied the dust properties present in the Vulture Head nebula, a collection of dust and gas 420 light years from Earth. The team observed the nebula with the Discovery Channel Telescope, a 4.3-meter telescope located south of Flagstaff, overlooking the Verde Valley. It is the fifth largest telescope in the continental United States and one of the most technologically advanced.

“To understand the evolution of the universe, it’s important to understand the galaxy evolution and how stars are formed,” said lead researcher Dr. Aditya Togi, a former UT doctoral student who is now a research assistant professor at the University of Texas at San Antonio. “If you know dust properties of the cloud, you can better understand star formation.”

In one of the first detailed images of the Vulture Head nebula, the cloud is illuminated by the faint starlight of the Milky Way and couldn’t have been captured in this detail without the power of the Discovery Channel Telescope. Dr. Aditya G. Togi took this photo.

The research team also included Dr. Adolf N. Witt, UT professor emeritus of astronomy, and Demi St. John, an undergraduate student from Murray State University. St. John, selected by the UT Physics and Astronomy Department to join the team, was partof the Research Experiences for Undergraduates program and funded through a National Science Foundation grant. She is in herfirst year of graduate school at Montana State University.

The team chose to observe the nebula with the Discovery Channel Telescope to test a model developed by French astronomers about the types and properties of dust particles. No one had ever tested those models through observation.

The French model posited that certain dust grains have specific properties. But the astronomers didn’t know for sure what types of dust grains were in the nebula or what size, temperature or density they were, Togi said.

The UT team measured the temperature and mass of the nebula’s dust and found that the dust grains in the cloud closely matched the properties predicted by three dust grain models in the French astronomer’s work. The research confirmed most of the model’s predictions and led the astronomers to new understandings about the dust particles that form stars.

They also learned that the cloud had something called “core shine.” The team knew that in order to scatter the light that creates core shine, some of the dust grains had to be larger than normally encountered in interstellar space. They found that the grains were more complex or “evolved.” They were coated with ice and frozen gases and had grown to about 100 times the volume of a typical interstellar dust grain.

“In order to reach this grain growth, the cloud must be at least a million years old,” Witt said.

Access to the Discovery Channel Telescope was crucial to this research. It’s also a powerful tool when attracting graduate students and young faculty.

“To be truly competitive, to have a first-rate program, you’ve got to have this kind of access to a first-class instrument,” Witt said.

UT is scheduled to host the annual Discovery Channel Telescope partner board meeting Friday and Saturday, Dec. 8 and 9, at the Driscoll Alumni Center. About a dozen representatives from UT, the Lowell Observatory, Boston University, Yale University, the University of Maryland, Northern Arizona University and the University of Texas at Austin will meet to discuss shared governance of the telescope and the best scientific uses of the instrument.

The Discovery Channel Telescope partnership has been a boon to UT astronomers and helped put the astronomy department on the map.

“Our astronomy program at Toledo is on an accelerating path,” said Dr. J.D. Smith, UT professor of astronomy, who is planning the board meeting. “We’re being recognized nationally and internationally, and this partnership is a big part of the reason why.”


Researchers study link between lung cancer, thrombosis

CLAIRE MEIKLE | SPECIAL TO THE BLADE
PUBLISHED ON Nov. 6, 2017

Cancer is the second leading cause of death in the United States, but did you know that many of these deaths are because of blood clotting?

Clots form when specialized blood cells called platelets detect a tissue injury or receive a clotting signal from another cell. Platelets then become activated, releasing proteins into the blood and onto their own surface. These surface proteins act like glue, causing platelets to stick to each other and to blood vessel walls. The platelets form a plug to patch the torn blood vessel. The platelet proteins released into the blood will attract more platelets and immune cells to the injured site and help the wound to heal.

Dr. Claire Meikle is researching how platelets contribute to thrombosis in cancer patients.
UNIVERSITY OF TOLEDO

Blood clotting is important to stop bleeding and heal injuries like cuts and scrapes, but sometimes clots form inside the blood vessel, blocking blood flow. When a clot forms inside a blood vessel, it prevents delivery of oxygen and nutrients to organs like the heart or brain. This kind of clot, called thrombosis, can lead to serious problems, including heart attacks and strokes.

Have you ever been warned about blood clots when you take a long airplane or car ride? Sitting still for an extended period of time allows blood to pool in your legs and reduces blood flow throughout the body. Because the blood isn’t moving, it increases risk of clots forming in the leg veins, a condition called deep vein thrombosis.

These clots are especially dangerous because they can grow to be very large and, if dislodged from the leg, they can travel through the bloodstream and get stuck in the smaller blood vessels in the lungs. This means that the blood will not be able to take fresh oxygen from the lungs to other organs and tissues in the body.

In healthy, active people risk of deep vein thrombosis is very low, and standing and walking around can be enough to prevent leg clots from forming. However, certain diseases can also make deep vein thrombosis more likely. Cancer patients are at especially high risk of thrombosis. We don’t know exactly why this is, but researchers are studying how cancer cells can make platelets more likely to form a clot. It is thought that cancer cells send pro-clotting signals to platelets, leading to a phenomenon called cancer-associated thrombosis.

Cancer patients are about five times more likely to experience thrombosis than healthy people. In fact, thrombosis occurs in as many as 20 percent of cancer patients, causing thousands of deaths each year. Chemotherapy used to treat cancer further increases the risk of thrombosis.

What can doctors do to help prevent cancer-associated thrombosis? First, clinical lab tests are used to measure a patient’s risk for clotting. In high-risk patients, drugs such as heparin can help to reduce clot formation. However, cancer patients taking these drugs are still at higher risk for clotting than people who don’t have cancer. Other health risks, including increased bleeding, are associated with taking heparin for an extended time. A better understanding of what causes clotting in cancer patients could help us develop a safer and more effective way to prevent these clots from occurring.

Platelets also help cancer cells spread to new sites in the body, a process called metastasis. Platelets do this by physically protecting cancer cells from being detected and then killed by other immune cells. Activated platelets can also release proteins that help neighboring blood vessels grow and help cancer cells survive as the cancer spreads. On top of all of this, cancer cells can trigger platelets to activate even more, increasing the risk of cancer spread and more blood clotting. This creates a vicious cycle of platelet activation and cancer spread. We don’t yet know how this cycle starts, or how to prevent it.

My research with Randall Worth at the University of Toledo College of Medicine, formerly the Medical College of Ohio, focuses on how platelets contribute to thrombosis in cancer patients, and how platelets in cancer patients differ from platelets in healthy people.

Lung cancer is the No. 1 cancer killer in the United States, and lung cancer patients are among those with the highest risk of clotting, so I am focusing on this high-risk population for my research.

I obtain blood samples from patients who have lung cancer and from healthy volunteers. I then analyze the platelets by labeling different kinds of cells with different colors, which can then be detected by a laser in a special machine. The machine will count the cells of each color. I can then compare the data across patients to look for differences.

I have found that platelets alone are not more likely to form clots in cancer patients, but they are more likely to interact with other immune cells. My next step will be to determine the mechanism of how platelets attach to immune cells. I will also explore how this attachment might affect platelet activity and the risk of thrombosis.

Further research will help us understand why lung cancer patients are more likely to develop a clot, and what we can do to prevent clots from forming. Our goal is to identify specific proteins that are involved in these cancer-specific interactions. This would allow us to develop a drug to stop only the interactions that lead to thrombosis while allowing platelets to continue doing their usual job of healing cuts and scrapes.

Additionally, this research could help doctors understand when it could be helpful to prescribe a drug that inhibits platelet activation. We anticipate that our work will help prevent clotting in high-risk patients and, ultimately, save lives.

Claire Meikle is an M.D./PhD student in the department of medical microbiology and immunology in the University of Toledo College of Medicine and Life Sciences Biomedical Science Program. Ms. Meikle is doing her research in the laboratory of Randall Worth. For more information, contact Claire.Meikle@rockets.utoledo.edu or go to utoledo.edu/med/grad/biomedical.


Brandon Tucker, a member of our Michigan Community College Leadership Doctoral Cohort, Crain’s forty under 40 for the class of 2017

BRANDON TUCKER | CRAIN’S DETROIT
PUBLISHED ON SEPT. 29, 2017

Brandon Tucker has always had a passion to help others succeed. So when Washtenaw Community College received a $4.4 million Community College Skilled Trades Equipment Program (STEP) grant from the State of Michigan — matched by their board with $3.6 million — Tucker wanted it to mean more than building renovations and equipment.

Through Tucker’s leadership, the college retooled its curriculum to align with the new technology the grant brought in, focusing on autonomous and connected vehicles.

“Our goal at WCC is to help prepare the workforce for what is not coming, but is already here.” — Brandon Tucker

“We saw the need and where the industry was going, like the need to train the technicians that support the engineers,” Tucker said, also crediting WCC president Dr. Rose B. Bellanca for her vision. “Our goal at WCC is to help prepare the workforce for what is not coming, but is already here.”

The new direction also allows WCC to partner with organizations like University of Michigan’s MCity, the world’s first controlled environment designed to test connected and autonomous vehicle technologies, and the Square One Education Network, which provides grants to educators developing tomorrow’s workforce. These partnerships allow students to graduate from the program more well-rounded and with hands-on experience.

Tucker said the new program has received nothing but great reviews from both students and the industry since its 2016 launch.

“Everyone needs education, inspiration, and empowerment,” said Tucker, who is also an assistant preacher with a mission to serve. “Nothing excites me more than when a person achieves even greater success than they thought possible.”

Related Items BRANDON TUCKER, DEAN OF ADVANCED TECHNOLOGIES & PUBLIC SERVICE CAREERS, WASHTENAW COMMUNITY COLLEGE


Mengjie Wang, Ph.D. Student – Special to The Blade | Early puberty can lead to health problems later in life

MENGJIE WANG | SPECIAL TO THE BLADE
PUBLISHED ON Nov. 6, 2017

We all go through puberty, the period of time when children physically and emotionally develop into young adults. Puberty happens when a part of the brain called the hypothalamus tells the body to release male or female hormones. In response, height and weight increase, and male or female characteristics begin to develop.

Puberty is considered early if it occurs before a girl is 8 years old or a boy is 9 years old. Around the world, puberty is starting earlier than it once did. Today, about one in 5,000 children goes through early puberty. The known risks for these children can include childhood bullying for body changes, short adult height, and an increased risk of breast cancer.

A clearer understanding of all risks of early puberty is important to patients and physicians.

Mengjie Wang is a PhD graduate student at the University of Toledo College of Medicine and Life Sciences biomedical science program.

Central precocious puberty is a common type of early puberty that involves your hypothalamus. In most cases, we don’t yet know what causes this, but brain tumors, injury, or inflammation are some of the causes.

A child going through puberty needs enough energy to have normal development. An obese child actually provides more energy than the child needs for normal development. This extra energy sends incorrect signals to the hypothalamus for puberty to start. Obesity and early puberty are serious health issues in the United States.

I study how the hypothalamus part of your brain controls obesity, puberty, and reproduction in our lab at the University of Toledo College of Medicine and Life Sciences, formerly the Medical College of Ohio.

We overfed female mouse models by giving them high-fat- diets from the day they deliver their pups until weaning (21 days) to investigate the potential effects of obesity and overfeeding in breastfeeding mothers. Surprisingly, we found that overfeeding the mothers during breastfeeding can cause obesity in the pups and significantly advance the start of their puberty.

This is the first evidence showing that overfeeding during breastfeeding influences obesity and puberty in the offspring.

Does early puberty, caused by overfeeding, also cause other health problems? We did glucose (sugar) tolerance tests and insulin tolerance tests to determine if these pups would develop diabetes when they became adults at 3 months old. We measured blood glucose levels every 15 minutes after giving them a large dose of sugar. Surprisingly, we found that these overfed mice could not keep their glucose levels within normal range. After we gave them insulin, which usually lowers blood glucose, their blood glucose measure did not fall.

These results show that overfed mice from overfed mothers are glucose intolerant and insulin insensitive. This means that obese mice with early puberty also have increased risk of developing diabetes during adulthood.

We then performed a fertility test on the obese mice when they were 4 months old. This tests the adults’ ability to reproduce. Notably, these experiments showed that female mice have trouble getting pregnant and have fewer pups than normal. Therefore, our studies also show evidence that obesity-induced early puberty can also contribute to reproductive problems during adulthood.

Another important player in the effects of childhood obesity is something called Insulin-like growth factor-1 (IGF-1). This is a protein secreted from the liver that regulates body growth and puberty. The hypothalamus in your brain can sense changes in IGF-1 levels and provides feedback signals to regulate IGF-1. We know that there are specific cells in the hypothalamus, called leptin-responsive cells that have IGF-1 receptors. This means that these specific cells can receive signals from IGF-1.

We used research methods to delete the IGF- 1 receptors in those leptin-responsive cells in the hypothalamus and then we tested these mice. We discovered that loss of IGF-1 receptors in otherwise normal mice will cause decreased body weight, along with delayed puberty and reproductive problems. This is the first evidence that IGF-1 receptors in leptin-responsive cells in the brain is important to normal body weight, puberty, and reproduction.

Doctors don’t always follow the same patients from puberty to adult life. Therefore our findings can alert doctors and patients with early puberty that other health problems may arise after they become adults. Correct treatment and follow-up are both important for patients with early puberty.

Mengjie Wang is a PhD graduate student at the University of Toledo College of Medicine and Life Sciences biomedical science program. She is completing her doctoral studies in the Molecular Medicine track in the lab of Jennifer Hill. For details, email Mengjie.Wang@rockets.utoledo.edu or go to utoledo.edu/​med/​grad/​biomedical.


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.