School of Medicine

Wayne State University School of Medicine

Research Spotlights

Fu-Shin Yu, Ph.D.
Dec 12, 2013
Diabetes Mellitus, a metabolic disorder that affects nearly 170 million people worldwide, is characterized by chronic hyperglycemia that disrupts carbohydrate fat and protein metabolism resulting from defects in insulin secretion, insulin action or both. DM can cause long-term damage, dysfunction and even failure of various organs.

Patients with DM may develop corneal complications and delayed wound healing. This slow wound healing contributes to increased infections and the formation of bed sores and ulcers. Corneal complications include diabetic neuropathies and ocular complications that often lead to reduced vision or blindness.

A team of Wayne State University researchers recently developed several diabetic models to study impaired wound healing in diabetic corneas. Using a genome-wide cDNA array analysis, the group identified genes, their associated pathways and the networks affected by DM in corneal epithelial cells and their roles in wound closure. The findings may bring scientists one step closer to developing new treatments that may slow or thwart DM’s impact on vision.

The team, led by Fu-Shin Yu, Ph.D., professor of ophthalmology and director of research at the Kresge Eye Institute, has discovered transforming growth factor β (TGFβ) signaling as a major pathway affected by hyperglycemia in DM corneal epithelial cells. In addition, Dr. Yu and his team identified for the first time that wound-induced upregulation of TGFβ3 is dampened by hyperglycemia and that by adding TGFβ3 to the wound, epithelial wound closure was accelerated.

This discovery, published on line in the prestigious scientific journal Diabetes, may provide new treatment options for diabetic wound healing in tissues such in the cornea and skin.

“Delayed wound healing are major complications of diabetes, often leading to severe end results such as diabetic ulcers, losing a limb or going blind,” said Joan Dunbar, Ph.D., associate vice president for Technology Commercialization at Wayne State University. “Dr. Yu’s discovery of the genome-wide transcriptional analysis has allowed the development of composition and methods to treat negative effects of diabetes, which may ultimately promote healing of wounds, reduce the negative effects of diabetic neuropathies, and promote the health of the eye and maintenance of eye sight in diabetics. The findings in the cornea have a strong implication in the skin as they both have neuropathy and delayed wound healing.”

Wayne State University has filed a U.S. Provisional Patent application on Dr. Yu’s technology discovery.

Dr. Yu’s research was funded by a grant from the National Eye Institute of the National Institutes of Health, award number EY01869 and Research to Prevent Blindness. 
Kezhong Zhang, Ph.D.
Oct 23, 2013
Collaborating with researchers at the Northwestern University Feinberg School of Medicine in Chicago, a research team at the WSU School of Medicine led by Kezhong Zhang, Ph.D., has contributed to an important discovery in the inflammatory stress mechanism and specific inhibitor for the treatment of rheumatoid arthritis.

The team led by Dr. Zhang, associate professor of Molecular Medicine and Genetics and of Immunology & Microbiology, and the team led by Deyu Fang, Ph.D., associate professor of pathology at Northwestern University Feinberg School of Medicine, worked together to discover the key inflammatory stress response that drives the development of rheumatoid arthritis. Their studies revealed that inflammatory stimuli trigger cell surface toll-like receptors of macrophages, the white blood cells that subsequently activate the Unfolded Protein Response transducer IRE1a to promote arthritis syndrome in the tissues around the joints.

Their work identified a specific IRE1a inhibitor that can efficiently prevent arthritis in animal models.

The study, “Toll-like receptor-mediated IRE1a activation as a therapeutic target for inflammatory arthritis,” was published in the prestigious scientific journal EMBO. Dr. Zhang served as a corresponding author. The study can be read at http://www.nature.com/emboj/journal/v32/n18/full/emboj2013183a.html.

“This is a notable work in the understanding of the stress mechanism for the development of rheumatoid arthritis,” Dr. Zhang said. “For the first time, we revealed the molecular targets of Unfolded Protein Response and Toll-like Receptor signaling and their interaction mechanism in the progression of inflammatory arthritis. Our study not only identified previously unknown molecular targets, but also pointed out a specific inhibitor that can efficiently suppress arthritis.”

Dr. Zhang said the next step toward the development of therapeutics may be testing the effects of specific inhibitors of Unfolded Protein Response in curing inflammatory arthritis with animal models and clinical trials.

Rheumatoid arthritis is an autoimmune disease that causes a chronic, systemic inflammatory disorder that can affect many tissues and organs, but principally flexible joints. Rheumatoid arthritis is one of the most common rheumatic diseases, affecting approximately 1.3 million people in the United States. The disease is three times more common in women than men and afflicts people of all races. The disease can begin at any age, but it often occurs in adults after age 40 and before age 60. The cause is unknown.

The disease is a costly one for the nation. According to the Arthritis Foundation, arthritis and rheumatic conditions cost the U.S. economy $128 billion annually, including $80.8 billion in medical expenditures and $47 billion in lost earnings.

Additional personnel at WSU who participated in this project include graduate students Ze Zheng and Aditya Dandekar.

Parts of this research were supported by National Institutes of Health grants (AI079056, DK083050, DK090313 and ES017829) and an American Heart Association grant (09GRNT2280479).
Omar Khan, M.D.
Sep 17, 2013
A groundbreaking study in multiple sclerosis focusing on “remyelination in the brain” has been initiated by Omar Khan, M.D., professor and chair of neurology at the Wayne State University School of Medicine.

“This is a novel approach in the treatment of multiple sclerosis, which is characterized by diffuse demyelination and axonal loss in the central nervous system,” said Dr. Khan, who also serves as director of the Multiple Sclerosis Center and director of the Sastry Foundation Advanced Imaging Laboratory. “In this study, we are targeting remyelination in the central nervous system.”

Dr. Khan noted that there are 10 United States Food and Drug Administration-approved treatments for multiple sclerosis, none with any well-characterized reparative or remyelinating potential. Those treatments primarily focus on altering the behavior of the immune system and target inflammation.

However, this new approach targets remyelination in the central nervous system using a humanized monoclonal antibody that binds to the semaphorin 4D, a member of the semaphorin family of proteins and an important mediator of axonal growth cone guidance. Semaphorin-induced signaling also has been shown to induce growth cone collapse of neurons and apoptosis of neural precursors, and to induce process extension collapse and apoptosis of oligodendrocytes. Semaphorins consist of a family of soluble and membrane-bound proteins that were originally defined as axonal-guidance factors. These proteins play important roles in establishing precise connections between neurons and their appropriate targets.

“Therefore, it is a plausible target with the realistic goal of achieving remyelination,” Dr. Khan said. “This is a paradigm shift and the start of the next generation of therapies to treat multiple sclerosis that will change its focus to repair rather than inflammation.”

The brain can largely be divided into gray and white areas. Neurons are located in the gray area, and the white parts are where neurons send their axons – similar to electrical cables carrying messages – to communicate with other neurons and bring messages from the brain to muscles. The white parts of the brain are white because a cell type called oligodendrocytes makes a cholesterol-rich membrane called myelin that coats the axons. The myelin’s function is to insulate the axons, similar to the plastic sheath coating electrical cables. In addition, the myelin speeds communication along axons and makes that communication more reliable. In patients with MS, their immune system attacks the myelin sheathing. The subsequent degradation leads to the messages from the brain to other parts of the body leaking and derailing from their intended target.

Restoring the myelin sheathing is the goal of Dr. Khan’s new study.

The Wayne State University Multiple Sclerosis Center, in collaboration with Vaccinex, a privately-held biotechnology company headquartered in Rochester, N. Y., initiated this early stage dose-defining study, monitored by the FDA.

“If successful, this will lead to large scale studies with this molecule targeting remyelination in the brain as a primary focus, detected by advanced imaging techniques such as magnetization transfer ratio,” Dr. Khan said. “The real challenge will be to reverse or reduce conduction blocks in the demyelinated nerve that may translate into neurologic improvement. If we could achieve that with this approach, it opens the door for hundreds of thousands of multiple sclerosis patients for whom no therapy is currently effective. This may also provide a unique opportunity in combining therapies with different mechanistic approaches.”

WSU is home to the only MS center in Michigan and among the 10 sites in the world undertaking this translational initiative. The center is among the top five MS centers in the U. S., with more than 4,000 patients. The center is involved in cutting-edge immunologic, genetic, MR imaging and therapeutic studies.

Dr. Khan said only three molecules in the world, including this monoclonal antibody, are being investigated in patients with multiple sclerosis that focus on remyelination.

“It is humbling to lead such a unique groundbreaking effort and that Wayne State University is one of the few centers in the world that are participating in this next true generation translational research,” he said. “The patients are observed over night at Harper University Hospital, which has been a great partner in facilitating this research endeavor.”

Multiple sclerosis affects more than 500,000 people (or one in 600) in the U.S. and more than 2 million worldwide. After trauma, it is the most common cause of disability in young adults. While there is no cure, several treatments are approved for the relapsing form of multiple sclerosis that reduces the frequency of flare-ups and slows disease progression.

For further information regarding the Wayne State University Multiple Sclerosis Center and this study, call 313-745-7186. To make an appointment with the neurologists of the Wayne State University Physician Group specializing in multiple sclerosis, call 313-745-4275.
Research Spotlight: Avraham Raz, Ph.D.
Sep 16, 2013

In the realm of biotherapeutics and natural plant therapy, holy basil could be the next big breakthrough in the field’s bustling anticancer movement.

A team of Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute researchers in Detroit has shown in an experimental tumor system that ocimum gratissimum, also known as African basil, inhibits the growth of human breast carcinoma cells.

The discovery could lead to clinical trials using the plant in concentrated form for treatment of breast cancer, and possibly other types of cancer.

Even cooking with the plant or eating it raw could have health benefits, said principal investigator Avraham Raz, Ph.D., a professor of pathology, radiation oncology and oncology in the WSU School of Medicine.

“We will know after the clinical trial. This drug can be consumed continuously, as it has no side effects and it is non-toxic,” Dr. Raz said.

The study, “Ocimum gratissimum retards breast cancer growth and progression and is a natural inhibitor of matrix metalloproteases,” is on the May cover of the science journal Cancer Biology & Therapy.

The plant, a dietary herb from the mint family Lameacea, is already used for its pharmacologic properties, including anticancer activity. It is absent in the continental United States but grows wild in Hawaii, according to the U.S. Department of Agriculture’s Natural Resources Conservation Service.

The WSU study shows that the herb inhibits the degrading enzyme responsible for facilitating breast cancer invasion and metastasis to other parts of the body, Dr. Raz said. The enzyme, matrix metalloproteases, or MMPs, is a family of at least 28 structurally and functionally-related zinc-dependent endoproteinases, which selectively degrade various components of extracellular matrix and lead to cancer cell growth according to the study article. Of the various MMP types thought to be involved in cancer, the WSU team focused on MMP-2 and MMP-9, because they are overexpressed in a variety of malignant tumors, and their expression and activities are often associated with aggressive tumors and a poor prognosis for patients. Elevated levels of both are found in breast, brain, ovarian, pancreas, colorectal, bladder, prostate, lung cancers and melanoma. The study reports that ocimum gratissimum inhibits cancer grow, partly due to its property as a natural, non-toxic inhibitor of MMP-2 and MMP-9.

The study is on the cutting edge of plant therapy and the biotherapeutics revolution, Dr. Raz said.

"Many traditional or folk remedies have a basis in reality – that is, they work – and are the backbone of modern medicine,” he added.

In addition to Dr. Raz, the study team included researchers from the WSU School of Medicine’s Department of Pathology and Department of Oncology; the WSU College of Engineering’s Department of Biological and Chemical Engineering; the WSU College of Liberal Arts and Sciences’ Department of Chemistry, as well as a researcher from the Chongqing University of Education in China.

The study was funded by a National Cancer Institute grant (R37CA046120-19).
Andre Konski, M.D., M.B.A.
May 30, 2013

Women undergoing radiotherapy for locally advanced esophageal cancer are three and a half times more likely to develop treatment-related heart problems than their male counterparts, said researchers at the Wayne State University School of Medicine.

“It’s a women’s health issue,” said Andre Konski, M.D., M.B.A., professor and chair of the WSU Department of Radiation Oncology. “In the theme of personalized medicine, we need to personalize not only for diseases, but for the gender of the patients.”

Dr. Konski, a member of the Barbara Ann Karmanos Cancer Institute, presented the results of the study, “Dosimetric modeling of cardiac toxicity in patients with esophageal cancer receiving chemoradiotherapy,” at the European Society for Radiotherapy and Oncology forum April 19-21 in Geneva, Switzerland.

The study is the largest of its kind to date. The study helps set the stage to help understand how the role new drugs for locally advanced esophageal cancer, including trastuzumab (brand name Herceptin), may play in increased cardiac toxicity rates.

The basic toxicity rates noted in the presentation are in line with other published studies in the United States. But the gender-biased results were a surprise to Dr. Konski and his study colleagues.

“This just sort of came out. We saw it and thought, ‘Wow, that’s interesting.’ We weren’t even looking for it, to be honest,” he said.

The group retrospectively reviewed the clinical information of 37 females and 113 males from 37 to 87 years old with locally advanced esophageal cancer undergoing pre-operative or definitive chemoradiotherapy from June 2002 to November 2012 at the Barbara Ann Karmanos Cancer Center in Detroit or the Fox Chase Cancer Center in Philadelphia. Chemotherapy was at the discretion of the treating medical oncologist. Of that group, 34 patients, or 23 percent, developed some form of cardiac toxicity from 1.2 to 28.9 months after treatment, including 13 females and 21 males. The women developed the toxicity at a lower dose of radiation compared to the men. Twenty-seven of the 34 patients developed radiation-induced pericardial disease, or fluid around the heart.

“Most of these patients were without symptoms,” he said. “If the pericardial effusion gets large, it can be life-threatening.”

Two patients developed radiation-induced coronary artery disease, three patients developed cardiomyopathy and two patients developed problems in the heart’s conduction system. While the presentation was received with interest, more evidence is needed to support changes to the current standard of care for patients, Dr. Konski said. In a study abstract, the researchers suggest further work be done, both to clarify the dose resulting in toxicity to each cardiac structure necessary to result in cardiac toxicity, and to understand why the difference in men and women exists. The researchers are now working on a manuscript for publication.

Moriah Thomason, Ph.D.
Feb 20, 2013
Wayne State University School of Medicine researchers have shown for the first time that brain connectivity in human fetuses can be measured, which could translate into new ways to diagnose, prevent and treat brain disorders like autism, attention deficit hyperactivity disorder, dyslexia and cognitive impairments in early life.

A collaborative project between Wayne State University and the Perinatology Research Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health led to this major discovery. The team, led by neuroscientist Moriah Thomason, Ph.D., assistant professor of Pediatrics at the WSU School of Medicine and director of the Perinatal Neural Connectivity Unit of the PRB, applied functional magnetic resonance imaging to study when communication or connectivity between areas of the brain emerge during human fetal life. Extremely challenging to perform, the research discovered that connectivity is already present during fetal life and becomes stronger during fetal development.

“Many brain disorders are thought to arise from disrupted communication in brain networks,” Dr. Thomason said. “Autism, ADHD and dyslexia, for example, have all been associated with disrupted brain connections. Therefore, it is of great importance to understand how these networks form and what events can impact the formation of networks and their connectivity.”

The study, “Cross-Hemispheric Functional Connectivity in the Human Fetal Brain,” was published in the Feb. 20 issue of Science Translational Medicine, a journal of the American Association for the Advancement of Science. The key findings of this study are:

• Connections between the right and left sides of the brain became stronger as fetuses matured.

• Short distance connections were more strongly connected than long-range connections in brain networks.

“By studying communication signals of the brain in healthy human fetuses, we are able, for the first time, to observe and measure the formation of these networks at the beginning of life,” Dr. Thomason said. While network connections in adults are well-established, in children, the networks are still developing.

Dr. Thomason’s team pioneered several techniques to overcome the challenges of scanning fetuses without compromising the health and safety of the mother or her child. Researchers obtained functional MRI connectivity diagrams for more than 80 regions in the fetal brain.

“When we began (in November 2012), we did not even know if these communication signals could be measured in the human fetus,” Dr. Thomason said.

The study reveals fetuses are forming connections before they’re born, and that these span shorter distances before they expand to connect widely distributed brain areas.

The team will now work to further define the order and timing of how brain networks are formed in utero, and compare the development of these brain networks in fetuses with disease, illness or unwanted exposures during pregnancy to determine how neural connection development is disrupted.

“A major motivation for this study was to understand the reasons why premature babies are at risk for cerebral palsy and other neurologic disorders,” said Roberto Romero, M.D., D.Med.Sci., chief of the Perinatology Research Branch, which focuses on the prevention of preterm birth and its long-term consequences. “More than half of preterm children require special assistance in the classroom: 20 percent are in special education and 50 percent repeat at least one grade in high school. We believe that insults (such as “silent” intrauterine infection or fetal oxygen deficiency) can affect the development of brain connectivity in utero, and this accounts for many of these disorders. The study published today is part of ongoing research to determine whether insults during fetal life have an effect on the brain, and how we can prevent long-term consequences.”

The MRI examinations were performed at WSU’s Vainutis Vaitkevicius, M.D. Magnetic Resonance Research Facility, located at Harper University Hospital in Detroit, under the direction of E. Mark Haacke, Ph.D., a WSU professor of Radiology and Biomedical Engineering. The research was supported in part by the Merrill Palmer Skillman Institute for Child and Family Development, the Kellogg Foundation, the WSU Department of Pediatrics and the NICHD.

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