- Nihar Nayak, D.V.M., Ph.D.
- Oct 28, 2014
A team of researchers led by a Wayne State University School of Medicine associate professor of obstetrics and gynecology has published findings that provide novel insight into the cause of preeclampsia, the leading cause of maternal and infant death worldwide, a discovery that could lead to the development of new therapeutic treatments.
Nihar Nayak, D.V.M., Ph.D., is the principal investigator of the study, “Endometrial VEGF induces placental sFLT1 and leads to pregnancy complications,” published Oct. 20 in the online version of The Journal of Clinical Investigation.
“Preeclampsia is a leading cause of maternal and fetal morbidity and mortality worldwide, yet its pathogenesis is still poorly understood,” Dr. Nayak said. “Many studies have suggested that elevated circulating levels of sFlt1 (a tyrosine kinase protein that disables proteins essential to blood vessel growth) contribute to the maternal symptoms of vascular dysfunction that characterize preeclampsia, but the molecular underpinnings of sFlt1 upregulation in preeclampsia have so far been elusive. Our manuscript describes the novel, field-changing finding that vascular endothelial growth factor, or VEGF, of maternal origin can stimulate soluble sFlt1 production by the placenta and that this signaling is involved in the cause of preeclampsia.”
Preeclampsia is a sudden increase in blood pressure after the 20th week of pregnancy. Indicated by a sudden increase in blood pressure and protein in the urine, preeclampsia warning signs, in addition to elevated blood pressure, can include headaches, swelling in the face and hands, blurred vision, chest pain and shortness of breath. While the condition can manifest within a few hours, some women report few or no symptoms.
The condition is responsible for 76,000 maternal deaths and more than 500,000 infant deaths every year, according to estimates from the Preeclampsia Foundation. It can affect the liver, kidney and brain. Some mothers develop seizures (eclampsia) and suffer intracranial hemorrhage, the main cause of death in those who develop the disorder. Some women develop blindness. The babies of preeclamptic mothers are affected by the condition and may develop intrauterine growth restriction or die in utero.
Many experts believe preeclampsia results from insufficient blood supply to the uterus and placenta, causing the development of high blood pressure. The increase in maternal blood pressure is a compensatory response to improve the condition of the fetus. Preeclampsia may have evolved to protect the infant, but when the disease is out of control it threatens the health of the mother. The earlier the disease starts in pregnancy, the worse the outcome can be for the baby and mother. Women with preeclampsia often do not feel effects until the condition is severe and becomes life-threatening. Effects on the mother include cardiac problems, possible brain hemorrhage, acute renal failure, blood clotting problems and possible blindness. If left undetected, the condition can progress to eclampsia and the mother may begin convulsing. For the fetus, preeclampsia has been connected to a reduction in placental blood flow, resulting in physical and mental disability, the slowing of fetal development, and in severe cases, infants may be stillborn.
While VEGF is essential for normal embryonic development, Dr. Nayak said, his team’s research has demonstrated that even mild elevation of VEGF levels during early pregnancy can cause severe placental vascular damage and embryonic lethality. The results show that modest increases in VEGF could also be a primary trigger for elevation of placental sFlt1 expression, leading to preeclampsia.
Furthermore, the findings indicate that sFLT1 plays an essential role in maintaining vascular integrity in the placenta in later stages of pregnancy and suggest that overproduction of sFlt1 in preeclampsia, although damaging to the mother, serves a critical protective function for the placenta and fetus by “sequestering” excess maternal VEGF.
According to the Preeclampsia Foundation, the condition, also known as toxemia or pregnancy-induced hypertension, affects 5 percent to 8 percent of pregnancies. Left untreated or undetected, preeclampsia can rapidly lead to eclampsia, one of the top five causes of maternal death and infant illness and death. Approximately 13 percent of all maternal deaths worldwide – the death of a mother every 12 minutes – have been attributed to eclampsia. The foundation reports that preeclampsia is responsible for nearly 18 percent of all maternal deaths in the United States.
Even if treated successfully, preeclampsia can bring future health problems for mothers. Women who have had preeclampsia have double the risk for heart disease and stroke over the next five to 15 years after they are treated.
The Preeclampsia Foundation estimates that in the United States about 10,500 babies die annually as a result of preeclampsia. The cost of the condition in the U.S., according to the foundation, is $7 billion annually, split between $3 billion a year in treating mothers and $4 billion a year for the cost of treating infants born prematurely because of preeclampsia.
The study, supported by the Wayne State University Perinatal Initiative, included research conducted by Stanford University School of Medicine, the University of Calgary, University of Utah and Yale University School of Medicine.
- Leonard Lipovich, Ph.D.
- Oct 6, 2014
The National Institutes of Health has selected Wayne State University School of Medicine researcher Leonard Lipovich, Ph.D., for its coveted Director’s New Innovator Award, a five-year, $2.3 million grant he will use from the National Cancer Institute to test a hypothesis that could lead to breakthrough methodologies to improve human health.
The project will identify primate-specific long non-coding ribonucleic acids, or lncRNAs, that are functional in cell growth and cell death, within the framework of human estrogen receptor positive breast cancer. The goal of the project, which has broad relevance to other nuclear hormone receptor pathways in human disease, is to reveal the extent to which non-conserved RNA genes contribute to cancer pathogenesis in humans.
Dr. Lipovich is a Detroit resident and an associate professor of the WSU Center for Molecular Medicine and Genetics and of the Department of Neurology.
The New Innovator Award mechanism was created by the NIH to support exceptionally creative new investigators who propose highly innovative, high-risk projects that have the potential for unusually high impact. Approximately 40 New Innovator awardees are selected each year. The small number of awards, along with the relatively high award amounts and the unconventional nature of the funded research, makes the program considerably more exclusive than the NIH’s more common R01 funding mechanism.
“Life, Death and Function: The Primate-Specific Long Non-Coding RNA Transcriptome,” will test whether evolutionarily young lncRNA genes – present in humans and some or all nonhuman primates, but absent in non-primates – are directly functional in positioning human estrogen receptor alpha positive breast cancer cells along the apoptosis-proliferation axis.
Long non-coding RNA is abundant in human cells. Long non-coding RNA genes often lack sequence conservation even between closely related species, in contrast to protein-coding genes, which are highly conserved across distant evolutionary lineages. Over the past several years, the Lipovich lab has been highlighting the primate-specificity of lncRNAs in diverse disease systems.
Targeting primate-specific lncRNAs therapeutically should result in fewer side effects than disrupting conserved pathways that current cancer drugs use. For selective chemotherapeutic agents that kill only breast cancer cells but not normal cells, pslncRNAs constitute a promising class of targets. The reason: these RNAs are young and have not yet had the time to deeply embed themselves in conserved protein-based networks over evolutionary time. Drug side effects may be a consequence of perturbing those conserved networks, Dr. Lipovich added.
“This is nothing less than a paradigm shift in cancer biology. Ever since Richard Nixon's lost ‘War on Cancer,’ proteins – and mouse models – have dominated the study of cancer,” he said. “Here, we systematically interrogate the contribution of non-protein-coding genes to cancer, with a focus on those that do not even exist in commonly used animal models.”
He is the first researcher from Wayne State University to receive the competitive award, which is so sought after he believed office staff was joking when they informed him of the honor.
“I am on the verge of realizing that a transformative, career-changing experience is already underway,” he said.
Dr. Lipovich, a proud graduate of Stuyvesant High School in New York City, received his bachelor’s degree from Cornell University in 1998, his doctorate from the University of Washington in 2003, and joined the School of Medicine faculty in 2007, working to build an internationally visible, high-profile research program. He is the only Wayne State faculty member to be selected by The Royal Society to chair one of its International Scientific Meetings, the lncRNA meeting that will take place outside of London in September 2015. Dr. Lipovich is also a funded co-investigator of ENCODE, or Encyclopedia of DNA Elements, the international consortium that serves as the official successor to the original Human Genome Project. He is in his second decade of working with the Japan-based Functional Annotation of the Mammalian Genome, or FANTOM project, and this year he joined the CHARGE, or Cohorts for Heart and Aging Research in Genomic Epidemiology, Consortium, singlehandedly bringing all these major international efforts to Wayne State through his laboratory.
“I have been arguing ever since the late 1990s, when I was a graduate student, that primate-specific, non-coding RNA genes are not junk, and that they can cause human disease,” he said. “I am profoundly and emphatically grateful for this opportunity to finally address exactly the problem that I've spent the past 15 years studying – the functional and mechanistic contribution of primate-specific long non-coding RNA genes to human phenotypic uniqueness, including human diseases that lack non-primate animal models.
“What ultimately inspires me the most is the potential of this project to empower a new era of post-genomic therapeutics,” Dr. Lipovich added. “I have a deep and abiding interest in actually improving human health and the human condition through therapeutic targeting of disease-causing lncRNAs, such as those that will be pinpointed by the newly funded work.”
Dr. Lipovich will attend the 2014 High Risk-High Reward Research Symposium, to be held Dec. 15-17 at the NIH campus in Bethesda, Md., as part of the award. The symposium will showcase presentations, poster sessions and networking opportunities for awardees.The research will be supported by National Cancer Institute Award 1DP2-CA196375.
- Steven Lipshultz, M.D.
- Jul 1, 2014
Recently published findings in Annals of Internal Medicine by Steven Lipshultz, M.D., Wayne State University professor and chair of pediatrics and pediatrician-in-chief at the Children’s Hospital of Michigan, part of the Detroit Medical Center, and colleagues could help to reduce health care charges while also protecting childhood cancer survivors from heart ailments caused by drug therapy.
That’s the “very exciting and very hopeful” bottom line of the recently published study, said co-author Dr. Lipshultz, who has spent more than 30 years studying the potential harmful impact -- or cardiotoxicity -- of drug therapies on the hearts of children who have survived cancer.
The study, “Cost-Effectiveness of the Children’s Oncology Group Long-Term Follow-up Screening Guidelines for Childhood Cancer Survivors at Risk for Treatment-Related Heart Failure,” reviewed data from patient histories to show that current standard medical guidelines for protecting childhood cancer survivors from drug treatment-related heart disease and heart failure later in life through periodic heart scans called echocardiographs are overly cautious.
According to the data, the frequency of such post-cancer screenings can be safely reduced for low-risk patients – with large cost-savings and little reduction in overall quality of patient care.
“The potential savings to be earned by reducing the frequency of echocardiographic screenings in patients who have survived childhood cancer seem quite promising,” Dr. Lipshultz said. “The data in our study on the cost-effectiveness of such screenings suggest that we could save 50 percent of the charges for this heart care screening, while also sparing these children from the rigors of needless heart scanning.”
While pointing out that total U.S. spending for health care exceeds $3 trillion a year and amounts to nearly 17 percent of the entire U.S. gross domestic product, Dr. Lipshultz described the breakthrough findings as “a classic example of how effective research in pediatric medicine can both assure the quality of patient care and help in the effort to keep medical costs under control.”
According to the findings, the guidelines for the frequency of heart scans among childhood cancer survivors – as devised in 2003 by the nation’s standard-setting Children’s Oncology Group – could be safely revised, so that instead of undergoing the scans every one, two or five years (depending on pertinent health factors), childhood cancer survivors would be scanned every two, four, five or 10 years.
While praising the study – http://annals.org/article.aspx?articleid=1872846 -- for its wide-ranging exploration of the issue, an accompanying AIM editorial noted that the new recommended frequency-of-scan schedule would lower “charges by 50 percent.”
The editorial went on to point out that “screening can be done cost-effectively and is highly likely to improve the quality and quantity of the patient’s life.”
The study has “important implications,” Dr. Lipshultz said, for the approximately 400,000 survivors of childhood cancer in the United States in 2014.
“The National Cancer Institute has estimated that one in every 530 young adults (ages 20 to 45) is a survivor of childhood cancer,” said the veteran researcher, who has published frequently over the years on the subject of cardiotoxic effects from cancer-related drug treatment in pediatric cancer survivors. “For these patients, making sure the long-lasting impact of drug therapy doesn’t lead to heart disease and heart failure later in life is vitally important.
“For childhood cancer survivors and their families, this new study is very good news, indeed – because it shows that many of them in the low-risk category can safely reduce the frequency of their heart screenings, with a significant reduction in accompanying costs.”
Dr. Lipshultz pointed out that asking childhood cancer survivors to undergo too-frequent heart scans also carries “a social cost.”
“The risk you run, if you ask these patients to have frequent scans, is that they may start to be seen by their friends and their families and their teachers at school as ‘different’ from the other kids around them. If that happens, these cancer survivors can even become youngsters whose lives are dominated by an exaggerated focus on their heart health.”
Dr. Lipshultz also said that the new study underlines the importance of “connecting research to clinical care in everything we do.
“If you want to see why that connection is so important,” he added, “just look at the ‘miracle’ in the treatment of pediatric leukemia care in this country during the past few decades. In 1970, only about 4 percent of childhood leukemia patients survived (the most prevalent form of the disease). But today, that same survival rate is over 90 percent. That’s been one of the biggest miracles in modern medicine – and it happened in large part because of a seamless connection that was achieved between research and clinical care.”
“As the pediatrician-in-chief, I feel very passionate about trying to connect research, education and quality patient care in every single thing we do at the Children’s Hospital of Michigan.”
- Fu-Shin Yu, Ph.D.
- Dec 12, 2013
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
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
“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.