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Hallie Dolin, Ph.D student, Laboratory work points to progress against sepsis | Special to The Blade

| SPECIAL TO THE BLADE
PUBLISHED ON Aug. 6, 2018

What do smallpox, the 1918 flu, and that infected cat scratch on your hand all have in common?

Your first thought is that all of them probably hurt, which is true. But the answer I’m looking for is that they’re all the result of inflammation in your body. While you might think of inflammation as a bad thing, it’s a normal process that is needed to fight off disease. The danger comes when normal inflammation spirals out of control.

Hallie Dolin
UNIVERSITY OF TOLEDO

Nearly 2,000 years ago, the doctor Celsus identified the four primary signs of inflammation as redness, swelling, heat, and pain. Those signs come from the release of molecules that rev up the body’s response to what it recognizes as foreign. You’ve most likely heard of sepsis, but probably are not aware of how it works.

Sepsis is usually caused by bacteria, which are tiny organisms that can only be seen through a microscope. Imagine you are a cell of E. coli, which is a very common infectious bacterium (the single form of ‘bacteria’). You’ve been left on a sharp surface, and so when someone accidentally cuts themselves deep enough to bleed, you and your fellow bacteria dive right in to feed and multiply. What you don’t know is that this person’s body knows you and your fellow bacteria are there, and it’s already sent an army after you.

As a common bacterium, you cannot hide from our immune system. You have molecules on your surface that our bodies have evolved to recognize over millions of years. Our cells, which you touched as you dived in, and our blood cells, touched your bacterial surface molecules and recognized you. Our cells have already set off an alarm. As you swim in the blood, proteins called cytokines, which trigger our inflammatory process, are running around our body to trigger alarms about your invasion. Our blood vessels around you are tightening and forming blood clots so you can’t move. Our blood itself is getting hotter and hotter as fever sets in, and as you look around, the white blood cells we sent out have come to swallow you whole.

You will probably die. However, in almost a third of cases of serious blood infection, so will the body you have infected.

Sepsis involves a serious infection in the bloodstream, and we have known about it for all of recorded history. We can track the proteins that make sepsis so dangerous, and recreate it in the lab. But for all that, over 700,000 cases occur every year in the United States, and over 200,000 are fatal. Why? Because the body’s inflammatory response isn’t specific to the invading bacteria.

The same inflammation that can kill bacteria so well can also damage our own organs so badly that they completely fail. This is the fatal side effect when our inflammatory responses spin out of control. Surviving sepsis also leaves people at risk of secondary infections like pneumonia, since all anti-inflammatory resources have been used up during the sepsis response.

Current treatment for sepsis is mostly supportive care, such as fluids and blood-pressure monitoring, combined with a lot of antibiotics. I study sepsis treatment as a member of Dr. Kevin Pan’s lab, in the Department of Medical Microbiology and Immunology at the University of Toledo. Our focus is the development of more effective anti-inflammatory treatments that curb out-of-control inflammatory responses.

We look at protective molecules in the blood that are responsible for ending inflammation after the bacteria aren’t dangerous any longer. Sepsis is deadly because the inflammatory response triggered by sepsis doesn’t respond to normal amounts of these anti-inflammatory proteins. My research involves telling the body to make more of these protective proteins to guard against destructive inflammation.

Specifically, I’m investigating a molecule called MAP kinase phosphatase 1, which acts as a brake for one of the most dangerous pathways of inflammation.

For the past two years, I’ve established an experimental test system for cells and animal models. I grow white blood cells from human and mouse cell lines in tissue culture plates, then add a chemical that triggers a sepsis response and a drug that we’ve found can increase the levels of MAP kinase phosphatase 1. Then I measure the response to these treatments to see how well the experimental procedure is working.

I also inject mouse models with the sepsis-inducing molecule, followed by drugs to increase levels of MAP kinase phosphatase 1. I then monitor the responses over several days to see if the mouse models remain alive, and how healthy they are.

We have promising results. Cells in culture that receive sepsis-inducing chemical along with the experimental anti-inflammatory drug make smaller amounts of inflammatory protein and look much healthier on a molecular level. The mouse models survive longer and their organs are healthier, which indicates a lower risk for medical complications.

Based on these results, our lab is working on a potential treatment for sepsis that might work better than current standard care. This treatment approach could help prevent the creation of antibiotic-resistant bacteria as well as treating sepsis, and could make the hospital safer for sepsis patients and all other patients.

Sepsis is dangerous, but I believe that we can fight it, and what we’ve seen in the lab so far indicates that better outcomes are possible.

Hallie Dolin is an M.D./ Ph.D. student in the Department of Medical Microbiology and Immunology in The University of Toledo College of Medicine and Life Sciences Biomedical Science Program. Hallie is doing her research in the laboratory of Dr. Kevin Pan. For more information, contact Hallie.Dolin@rockets.utoledo.edu or go to utoledo.edu/med/grad/biomedical.


Microenvironment plays a role in cancer progression By Kaitlyn Dvorak | Special to The Blade

| SPECIAL TO THE BLADE
PUBLISHED ON July 2, 2018

Breast cancer has been one of the hottest fields of scientific research for more than 50 years now, with widely recognized public campaigns to increase awareness and education. These combined efforts have led to much improved survival outcomes during this time. The five-year survival for earliest stages is close to 100 percent, 93 percent for the second earliest stage (2), and 72 percent for stage 3.

Kaitlyn Dvorak stands by a research poster describing the work she has done with trying to determine the role microenvironment plays in cancer progression.

Despite these new advances in early stage breast cancer, approximately 41,000 breast cancer patients were predicted to die in the United States this past year. These deaths are due to stage 4 cases, which usually include metastatic breast cancer.

Metastatic breast cancer is when cancer cells from the primary tumor enter the blood or lymph circulation system of the body and travel to distance sites to grow secondary tumors. This late-stage breast cancer usually has a poor outcome with a five-year survival of only 22 percent. Standard treatments for breast cancer at earlier stages are less effective against this late-stage metastatic disease, which motivated our lab to identify mechanisms to stop metastatic breast cancer.

Research goals for breast cancer research have been focused on figuring out different roles of DNA mutations, heredity, and hormones for predicting and treating this disease. We focused on the breast cancer cells.

In recent years, research questions began to include different surrounding cells and tissues for possible roles in the growth of breast cancer. This closely surrounding area, called the microenvironment, can take on some features similar to the cancer cells, creating a population of cells that are not fully cancerous but are also not quite normal. This microenvironment can release molecular factors that can increase tumor cell growth, supply nutrients to the tumor, and even increase cell movement — possibly increasing metastatic travel of breast cancer.

Our overall goal is to understand what drives cancer cells to move to other body sites. Breast tissue is composed of many different types of cells and structures which metastatic cancer cells must travel through to reach their new metastatic site before lodging and growing.

Much like our own skeleton, the cytoskeleton provides support for each of our cells. To travel successfully, a cancer cell must continually change its cytoskeleton, which is not set in a permanent position like our human skeleton.

A cell can alter each part of its cytoskeletal structure that is required for cell movement through specific tissue, and when that structure isn’t needed anymore, it is broken down. Specific proteins are required in the formation and retraction of each of these different cytoskeletal structures.

Our research is focused on how these structures can change. We now know that a protein called mDia2 is an important regulator of the cell cytoskeleton. The mDia2 protein helps to build and control cell structures required for moving through different microenvironments in the tissue.

One important question of our research group is to figure out if other cells in the local microenvironment can affect expression of mDia2 in breast cancer cells. In other words, does the microenvironment help control cancer cell movement by affecting regulators, such as mDia2, of the cancer cell cytoskeleton?

When we grow these other cells from the microenvironment in a special media in our laboratory, these cells release molecular factors into the media. This conditioned media is then used to replace the media that breast cancer cells grow in. This media switch allows us to examine what effects the conditioned media from noncancer cells has on breast cancer cells.

Indeed, when we add this conditioned media to breast cancer cells, we see increased cancer cell movement.

We can also use special plating conditions to grow these breast cancer cells into small clusters of cancer cells that are like a tumor. This allows us to investigate growth of cancer cells in a three dimensional way that is similar to tumors in patients, rather than just one layer of cells on a culture plate.

We now know that the cancer cell clusters also have increased movement through a surrounding matrix similar to our body’s tissues. Cancer cells in the body must travel through such tissues to metastasize. These results show us that conditioned media from other cells in the microenvironment can indeed drive breast cancer cells to more movement.

Next we asked if increased cancer cell movement was due to changes in the cytoskeleton. We looked at the cytoskeletal regulator mDia2 in breast cancer cells that had been treated with the conditioned media. We observed that this exposure caused expression of mDia2 to be lost and, most importantly, the breast cancer cells grew more slowly.

These results might seem like the opposite of increasing cell movement, however decreasing growth of breast cancer cells is known as “go versus grow.” This means cells that are moving are less likely to grow.

We believe that by carefully investigating the microenvironment around tumors, there is an opportunity to determine the possibility of metastasis. This knowledge will help to guide better treatment options.

Kaitlyn Dvorak earned her PhD in the University of Toledo College of Medicine and Life Sciences Biomedical Science Program this spring. She did her doctoral research in the laboratory of Dr. Kathryn Eisenmann in the Department of Cancer Biology. For more information, contact Kaitlyn.Dvorak@rockets.utoledo.edu or go to utoledo.edu/​med/​grad/​biomedical.


UT runner, Janelle Noe, takes 11th at NCAA Championships

Janelle Noe, a new graduate student in the Doctor of Physical Therapy program, and recipient of the 2018-2019 Robert R. Buell Memorial Scholarship, through the College of Graduate Studies, takes 11th at NCAA Championships.

UT News
PUBLISHED ON JUN 9th, 2018

Senior Janelle Noe wrapped up the NCAA Track and Field Championships Saturday with an 11th-place finish in the 1500m.

Noe crossed the line in 4:20.37 and was named Second-Team All-America following the race in Eugene, Ore.

With her finish, Noe claimed the best finish by a Rocket in the NCAA Championships since April Williams took eighth in the triple jump in 2007.

“I can’t feel anything but immense pride for what she’s accomplished this season,” Head Coach Linh Nguyen said. “For what she’s done this year, it’s been a dream season really, and I told her this morning that if we walk away from here and she finished last in the race today, we’re going to walk away happy and smiling. There’s no other way you can look at it; it was a huge success.

“Nothing’s given and I think she, more than anyone, knows that nothing beyond today is guaranteed,” Nguyen added. “I just want her to stay healthy. If she stays healthy and trains consistently, then I think she can do special things next year.”

Noe’s 4:10.83 time from Thursday qualified her for the USA Track and Field Championships. A decision whether or not she will participate will be made soon.


Jeremy Holloway, doctoral student Reflections on China: Teaching English, touring with Yale Alley Cats, showing Rocket pride

UT News
PUBLISHED ON MAR. 30, 2018

Since October 2017, I have had the opportunity through the support of a company called Education Group Central to teach middle school students in China English as a second language online. The experience was enriching as I would often pick up the guitar and teach the students a new American song. I never thought I would have the opportunity to visit and see them face to face.

Jeremy Holloway took a selfie with some of his students.

On March 10, I was invited to travel on my first visit to China in order to meet all my students whom I had been teaching on the screen. The experience was surreal. I’m sure it was the same for them. As we all met each other for the first time, we were star-struck; it was like we met someone we had only been watching in the movies.

My classrooms were in multiple cities all over China, so I visited them all. The first stop was in Beijing, then by plane to Zhongshan. From there, I traveled by train to Guiyang, then to Xi’an, and then back to Beijing.

I had the opportunity to visit the Great Wall of China and the Forbidden Palace in Beijing. I also had the opportunity to see the Terracotta Army Sculpture Museum in Xi’an. I tried everything from hot pot and Chinese burgers to Peking duck. It was phenomenal. Since some of the distances between cities was farther than a trip from New York to Orlando, Fla., I had the opportunity to experience all kinds of climates from areas with the same temperature as Toledo to areas with T-shirt weather and palm trees.

I visited the schools and taught each class one lesson, and then we had time for questions and answers. Most of the students asked me about my experience in China, what cities I visited, and how I liked the food. I felt like a celebrity as they crowded around me to ask for my autograph. A very humbling experience indeed, but we all enjoyed ourselves.

Jeremy Holloway took a selfie with the Yale Alley Cats on the Great Wall of China.

What made my experience very unique on top of visiting the students — I was placed on a tour with a group called the Yale Alley Cats. The team of undergraduate male Yale students is part of a group that started at the school in 1943. It was fascinating to spend time with these students and ask them questions about their experience applying and getting into Yale. Some of the students shared how they took the SAT and the ACT 19 times before entering, and another student said he only took the test a couple of times, but wrote a good essay. The students were extremely talented in different ways, from knowing two or three languages to their well-mannered behavior everywhere they went.

But the one thing I learned from them that was fascinating was their common decisions in choosing Yale because the university let them pursue the arts along with STEMM (science, technology, engineering, math and medicine). They shared how they felt other Ivy League schools only cared about the academics, but Yale strongly encouraged a balance of pursuing the arts like singing, dance, languages, etc., along with their academic interests. What I realized the most was the students were passionate about something they studied, and they credited that passion to why they really got accepted to Yale.

After I shared with them my joy of singing, they also graciously let me lead one of their songs during a dinner together. I sang “If I Ain’t Got You” by Alicia Keys with the Yale Alley Cats.

Sporting one of his favorite UT T-shirts, Jeremy Holloway had his photo taken on the Great Wall of China.

I was proud to represent The University of Toledo with these students. I shared with one Yale student how my father worked at The University of Toledo just so I could have the opportunity to go to school, and I feel like I am living out a legacy. My story was well-received, and it felt good to form a mutual relationship with these students through my story.

Something the Yale students attribute to their success in academics is something that I believe successful UT students can also attest to. It was refreshing to hear that their success in their academics at Yale, in their opinion, is still dependent on their involvement in student activities and groups on campus. None of the students thought it a good idea to lock themselves in a room and study all day. In fact, they shared how they met their best friends in this Yale singing group and that when they feel stressed from the heavy work they have to do, the time with their Alley Cat friends melts away their stress and gives them the balance and the fortitude they need to excel in their academics.

Most importantly, I find it crucial to understand that the name of a university is only relative to the goals you want to accomplish. I want University of Toledo students to understand how our pride in our university makes us stand side by side with the best of them. I would encourage each UT student to become crystal clear about his or her goals and treat The University of Toledo as a Harvard student treats Harvard because they understand that the university never made the people, but the people always make the university. Go Rockets!

Holloway is a doctoral student in the Judith Herb College of Education. Last year, he was honored with the 20 Under 40 Leadership Award, which recognizes Toledo community members 39 or younger who demonstrate exceptional leadership qualities. The UT alumnus received a bachelor of arts degree in Spanish and a bachelor of education degree in 2005, and a master’s degree in English as a second language in 2014.


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.”