- Moriah Thomason, Ph.D.
- Feb 20, 2013
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.
- Renu Kowluru, M.S., Ph.D.
- Jan 18, 2013
Dr. Kowluru’s study will investigate the role of epigenetic modifications of matrix metalloproteinase-9 in the development of diabetic retinopathy. She will test the hypothesis that alterations in the histone codes of retinal matrix metalloproteinase-9 in diabetes regulate its activation, and activated metalloproteinase-9 damages the mitochondria, resulting in the development of diabetic retinopathy.
“Our ultimate goal is to identify an adjuvant therapy that a patient can supplement their best possible glucose control and prevent the development of diabetic retinopathy,” Dr. Kowluru said.
Funding for the research study will assist in developing a stronger knowledge and understanding of diabetic retinopathy.
“Efforts are being put into developing the inhibitors of histone lysine demethylases,” Dr. Kowluru said. “Successful completion of our studies will provide a strong background for their use to prevent this sight-threatening complication of diabetes.”
In addition to this grant, Dr. Kowluru has been awarded two other RO1 grants to understand the role of mitochondrial damage, and NADPH oxidase in the pathogenesis of diabetic retinopathy.
- Kezhong Zhang, Ph.D.
- Nov 12, 2012
A team led by the Wayne State University School of Medicine’s Kezhong Zhang, Ph.D., has discovered why people living in areas with higher than normal levels of air pollution are at increased risk of developing metabolic disorders such as type 2 diabetes, obesity and atherosclerosis, the thickening of artery walls.
The study pinpoints the stress mechanism that causes air pollution to impair both lipid and glucose metabolism and insulin action in the liver. The team expects the work to have a major impact on health policy decision-making, clinical disease diagnosis and treatment.
“Our study indicated that those who work under high levels of PM2.5 exposure, such as truck drivers and car industry employees, have much higher risk to developing metabolic disease, such as obesity and type 2 diabetes,” Dr. Zhang said. PM2.5 is airborne particulate matter with an aerodynamic diameter smaller than 2.5 micrometers. It’s a mix of particles and gases from gasoline and diesel engines, together with dust from roads, tires and brakes.
His team worked with other groups in the School of Medicine’s Center for Molecular Medicine and Genetics, as well as researchers at Ohio State University. Dr. Zhang, assistant professor of Molecular Medicine and Genetics and of Immunology and Microbiology, is the project’s principal investigator.
“PM2.5 particles are the major toxic components of air pollution. PM2.5 pollution has major impact on public health for the general population in urban areas, especially for those who live in areas of intensive traffic or industrial activity. Recent epidemiological studies and clinical observations suggested that populations under high levels of PM2.5 exposure have much higher risk to develop cardiovascular disease and metabolic disease,” he said.
The risk is through liver-associated inflammatory stress and metabolic impairment caused by PM2.5. Manufacturing employees, truck drivers and others experiencing long-term daily road traffic should pay close attention to blood markers or liver enzymes that indicate metabolic disease.
“According to our findings, these individuals should adjust their diets and lifestyles to reduce the risk caused by air pollution,” he said.
Dr. Zhang suggests eating a diet high in antioxidants, especially strawberries.
The researchers also recommend that physicians and other health care professionals apply preventive therapeutic strategies or health care approaches toward the liver for patients exposed to regular air pollution.
The study, “Exposure to ambient particulate matter induces a NASH-like phenotype and impairs hepatic glucose metabolism in an animal model,” was published on line at www.sciencedirect.com, and is expected to appear in the January issue of the Journal of Hepatology.
In the study, the group exposed an animal model to real-world PM2.5 in Columbus, Ohio, where most of the PM2.5 components were attributed to long-range transport and traffic. In the United States, six of the top 25 cities considered most polluted between 2007 and 2011 were in the Midwest, as reported by the American Lung Association.
“Columbus, where the animals were exposed in this study, is a ‘perfect’ site to study the adverse health effects of PM2.5, and the levels and composition of PM2.5 from Columbus is a regional representative of Midwest source of air pollution in the United States,” Dr. Zhang said.
Recent epidemiologic studies have linked air pollution to the development of type 2 diabetes. Diabetes’ prevalence in the U.S. increased with increasing airborne particulate matter PM2.5 concentrations, as evidenced by a 1 percent increase in diabetes prevalence seen with a 10 μg/m3 (micrograms per cubic meter of air) increase in PM2.5 exposure, he said.
While most researchers in the field are studying the toxic effects of PM2.5 on lung and blood vessels, Dr. Zhang’s team studied the pathological effects and stress mechanisms of PM2.5 exposure on the liver, the organ of detoxification and metabolism closely associated with the development of metabolic disease.
The work revealed that PM2.5 exposure triggers inflammatory stress responses and impairs insulin signaling in the liver, leading to key features of non-alcoholic fatty liver disease, also referred to as non-alcoholic steatohepatitis, or NASH. It affects 2 percent to 5 percent of Americans, according to an April 2012 report of the National Digestive Diseases Information Clearinghouse, a service of the National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, with an additional 10 percent to 20 percent of Americans having fat in their liver with no inflammation or disease.The project is funded by NIH’s National Environmental Health Science Institute (grant Nos. ES017829, ES016588, ES017412) and National Institute of Diabetes and Digestive and Kidney Diseases (grant No. DK090313).
- Jeffrey Loeb, M.D., Ph.D.
- Oct 15, 2012
The SBEP started out with funds from the President’s Research Enhancement Fund and spanned neurology, neuroscience, genetics and computational biology. It since has been supported by multiple National Institutes of Health-funded grants aimed at identifying the underlying causes of epilepsy. It is uniquely integrated within the Comprehensive Epilepsy Program at the Wayne State School of Medicine and the Detroit Medical Center.
Under the guidance of Jeffrey Loeb, M.D., Ph.D., associate director of the Center for Molecular Medicine and Genetics and professor of Neurology, the project brings together researchers from different fields to create an interdisciplinary research program that targets the complex disease. The multifaceted program at Wayne State is like no other in the world, officials say, with two primary goals: improving clinical care and creating novel strategies for diagnosis and treatment of patients with epilepsy.
The three studies were published in high-impact journals and use human brain tissue research to identify new targets for drug development, generate a new animal model and identify a new class of drugs to treat the disease.
In the first study, “Layer-Specific CREB Target Gene Induction in Human Neocortical Epilepsy,” published recently in the Journal of Neuroscience, donated human brain samples were probed to identify 137 genes strongly associated with epileptic seizures.
Researchers showed that the most common pathway is activated in very specific layers of the cortex, and that it’s associated with increased numbers of synapses in those areas. Because epilepsy is a disease of abnormal neuronal synchrony, the finding could explain why some brain regions produce clinical seizures.
“Higher density of synapses may explain how abnormal epileptic discharges, or spikes, are formed, and in what layer,” Dr. Loeb said, adding that localizing the exact layer of the brain in which that process occurs is useful both for understanding the mechanism and for developing therapeutics.
The first study, which identified a new drug target for epilepsy, precipitated a second study that has found such a drug.
In the second study, “Electrical, Molecular and Behavioral Effects of Interictal Spiking in the Rat,” published recently in Neurobiology of Disease, SBEP researchers found that the same brain layers in the rat are activated as in the human tissues. They searched for a drug to target those layers. In fact, the first drug they tried, a compound called SL327 that has been used in nonhuman subjects to understand how memory works, “worked like a dream,” Dr. Loeb said.
“SL327 prevented spiking in rat brains,” he said, “which not only prevented seizures, but led to more normal behaviors as well.”
That finding led to collaborations between Dr. Loeb’s lab and Nash Boutros, M.D., professor of Psychiatry and Behavioral Neurosciences, and the Belgian drug company UCB.
“Whereas animals that developed epileptic spiking became hyperactive, those treated with the drug and had less spiking in their brains were more like normal animals,” he said. “Now whenever we screen for drugs for epilepsy, we look at behavior as well as epileptic activity.”
Noting that many seizure medicines are used to treat various psychiatric disorders, Dr. Loeb said the SBEP team’s latest round of work marks a “nice crossover” between psychiatry and neurology in the field of drugs related to epilepsy.
In the third study, published in Genetics, researchers say they have found “fascinating interrelationships” between “junk” long noncoding RNA and normal RNA that are regulated by human brain activity. That work has the potential to be translated into new genetic treatments for epilepsy.
“This study shows how the human brain deals with half of the human genome in its most important function, electrical activity, using human brain tissue from patients with epilepsy to understand the basic molecular processes of how the brain works, and what’s unique about human brains compared to the brains of less-developed species,” Dr. Loeb said.
The third study, titled “Activity-Dependent Human Brain Coding/Noncoding Gene Regulatory Networks,” is a collaborative effort between Dr. Loeb’s lab and Leonard Lipovich, Ph.D., assistant professor of Neurology and of Molecular Medicine and Genetics. It found that certain genes and their noncoding counterparts (which some researchers have called “junk”) are co-regulated, or turned on at the same time, with brain activity.
“This tells us that some of these noncoding genes may actually have functions in brain activity,” Dr. Loeb said. “In some, turning one on turns another one off. Some are regulatory and can be used to control plasticity genes — which are involved in memory, learning and behavior — with one of these novel, noncoding RNA genes.”
The synergy exhibited by the three studies, Dr. Loeb said, is testimony to the multidisciplinary nature of Wayne State’s systems biology platform, partly developed with a remarkable three-dimensional database created in cooperation with Farshad Fotouhi, Ph.D., dean of the College of Engineering, and Jing Hua, Ph.D., associate professor of Computer Science.
“SBEP is a cross-campus endeavor,” Dr. Loeb said. “These studies are the fruits of the labor of this consortium and only exist at WSU. The next steps will be translating these exciting findings into new treatments to prevent or even cure patients with epilepsy and other psychiatric disorders.”
The studies were funded by the National Institute of Neurological Diseases and Stroke of the National Institutes of Health grant Nos. R01NS045207, R01Ns05058802, F30NS049776; by the National Institute on Drug Abuse of the NIH, grant No. 1R03DA0262-01; and by the State of Michigan Joe Young Funds to the Department of Psychiatry and Behavioral Neurosciences, and were started with help from the WSU President’s Research Enhancement Fund.
- Leonard Lipovich, Ph.D.
- Sep 6, 2012
Dr. Leonard Lipovich’s determination to prove genetic matter once deemed “junk” has a place in clinical medicine is bringing the Wayne State University School of Medicine to the forefront of a burgeoning field occupying genome enthusiasts in the United States, Asia and Europe.
The work, on long non-coding ribonucleic acids, or lncRNAs, could lead to new therapeutics for cancer and other diseases.
“Long non-coding RNA genes comprise half of human genes. Most medical, therapeutic work so far has focused on normal, protein-coding genes. So, we – working as part of a multinational team of scientists - have just expanded, twofold, the set of genes that can be therapeutic targets,” he said.
The publication of two groundbreaking articles highlighting results from his lab at WSU’s Center for Molecular Medicine and Genetics is pushing Dr. Lipovich, and his lab’s fellow and graduate students, into the spotlight.
“For many years people pooh-poohed our field, saying that our long non-coding RNAs are either junk, or conventional protein-coding messenger RNAs that we failed to properly understand. We now demonstrate, using an experimental approach, that they are really non-protein-coding (never translated into protein) RNAs in human cells,” said Dr. Lipovich, Ph.D., assistant professor of Molecular Medicine and Genetics and of Neurology.
Dr. Lipovich is a joint last author on a paper on whole-genome translation testing of human lncRNAs, included in the September 2012 issue of Genome Research, the genetics and genomics field’s leading peer-reviewed journal. The September issue is dedicated to the latest phase of results from the Encyclopedia of DNA Elements (ENCODE) Consortium – an international human genomics effort that succeeded the completion of 2001’s Human Genome Project.
The paper sets a new standard for how to integrate RNA data with protein data in a way that has never been done. “My lab, through its computational work here at Wayne, did a vital part of the integration, developing a method that can be used in any future studies that intersect protein and RNA data genome-wide,” Dr. Lipovich said. “Unusual, rare lncRNA-encoded proteins, such as those we found, could be the results of incorrect lncRNA processing by cells in diseased tissues, and hence a huge resource of biomarkers for diagnostics.”
“Long non-coding RNAs are emerging as a huge part of primate, including human-specific, complexity or human phenotypic uniqueness. Yet, they play a critical role in regulating the conserved part of the genome,” said Emily Wood, a WSU Molecular Medicine and Genetics doctoral candidate who served as a second author on the lncRNA translation paper.
“It’s really on the edge of what’s known,” she added, calling the lncRNA field “the wild, wild West” right now.
“There is no unified model of how lncRNAs work,” she said. “We’re really interested in therapeutics in this lab. We’re also not working on a model organism. We’re looking at the activity of the human genome in actual human tissues.”
A National Human Genome Research Institute-funded consortium, international in scope and aided by funding from several countries in Europe and Asia, ENCODE is one of the two major collaborative groups to succeed the completion of the Human Genome Project in 2001, which gave science the ability to read nature's complete genetic blueprint for building a human being.
Abnormal translation – the unusual expression of proteins from RNAs that are not supposed to be protein templates -- clearly has the potential to emerge as a key trend in cancer and autoimmunity research soon, Dr. Lipovich said, and major genomics labs at Harvard Medical School and other top universities are working on complementary aspects of this biological problem.
WSU postdoctoral fellow Hui Jia, Ph.D., in the Lipovich Lab, and WSU Molecular Medicine and Genetics doctoral candidate Will Gundling, during his rotation in the lab last year, also contributed as co-authors of the article, titled “Long noncoding RNAs are rarely translated in two human cell lines.” Dr. Jia is a joint-first author of the paper.
“The energy in the lncRNA community is phenomenal,” Wood said. “It’s a really exciting time to be part of that community. It’s not a science that’s been around forever that we can fine tune. It’s really fun to be a student and be a part of it.”
An additional paper in September’s Genome Research co-written by Dr. Lipovich, “The GENCODE catalogue of human long non-coding RNAs: Analysis of their gene structure, evolution and expression,” presents the most authoritative reference catalog of noncoding-RNA genes ever constructed.
“It will be used by the entire international ENCODE Consortium as a foundation for functional studies linking this exciting new class of RNAs to human health and disease,” said Dr. Lipovich, a middle author on this large, international effort from ENCODE’s Analysis Working Group.
The ENCODE AWG is open to all academic, government and private sector scientists interested in participating in an open process to facilitate the comprehensive identification of the functional elements in the human genome sequence, and who agree to a variety of criteria.
In the GENCODE paper, he and his colleagues found that nearly 5,000 human lncRNAs are not conserved – meaning that there are no similar or identical sequences, in species outside of primates, to these genes. These primate-specific lncRNAs are, hence, absent in mice and other animals. This highlights the limitations of animal models, and the need to study humans to understand human disease, he said. This has major implications for the molecular basis of primate and human uniqueness – which just might be encoded in part by these new RNAs, he said.
Dr. Lipovich also is a member of the Japan-based international research consortium Functional Annotation of the Mammalian Genome, the other leading post-genomic effort. FANTOM, headquartered at the RIKEN (Japan Institute of Physical and Chemical Research) Omics Science Center in Yokohama, analyzes the mammalian transcriptome -- the complete set of all RNA molecules produced in one or a population of cells – using next-generation sequencing.
For FANTOM5, he contributes computational analysis of complex loci and lncRNA network validations. Other member institutions working with RIKEN – and WSU – on this project include Harvard, University of California at Berkeley, Sweden’s Karonlinska Institutet, The Roslin Institute at the University of Edinburgh, Scotland, and the United Kingdom’s Medical Research Council. Dr. Lipovich’s RIKEN collaboration started in 2004, when he joined FANTOM3 while a postdoctoral fellow at the Genome Institute of Singapore.
“WSU earned its ENCODE AWG membership because of the world-class computational genomics that I've been doing in my lab here since 2007 – methods and results that are valued by the FANTOM Consortium in Japan and that through FANTOM exposed us to other valuable collaborators -- such as ENCODE,” Dr. Lipovich said. The Lipovich Lab is the only laboratory in the entire State of Michigan to participate in both FANTOM and ENCODE, a prestigious distinction.
- Pratik Bhattacharya, M.D.
- Aug 16, 2012
This novel work, led by Pratik Bhattacharya, M.D., M.P.H., assistant professor of Neurology and the Stroke Quality Officer of the Detroit Medical Center, was recently published in the Journal of Neurological Sciences.
“We showed that low left ventricular ejection fraction may lead to cerebral grey matter injury,” Dr. Bhattacharya said.
Using fully automated software known as SIENA, Dr. Bhattacharya observed that the lower the cardiac ejection fraction, the lower the gray matter volume. This relationship was not observed for the cerebral white matter.
The discovery suggests the unique sensitivity of the cerebral gray matter to possible chronic hypoxic injury in patients with poor cardiac outflow. Further studies are needed to examine how to optimize strategies to treat cardiac failure, reduce or prevent further cortical injury.
The research was performed in the MR Image Analysis Laboratory of Omar Khan, M.D., professor and interim chair of Neurology, who is the senior author of the study. Dr. Khan said the findings are intriguing and provide a major opportunity to investigate mechanisms of cerebral gray matter injury in patients with varying degrees of heart failure.
The results the study could be extended to other conditions associated with states of chronic hypoxia, such as sleep apnea and chronic obstructive pulmonary disease, which affects millions of Americans. This may also provide clues into the cognitive impairment that is often reported in these patients.
Additionally, the study opens a window to examine cerebral gray matter injury in traumatic brain injury.
Dr. Bhattacharya and Dr. Khan plan to organize a major research project across disciplines to investigate cerebral gray matter injury in states of chronic hypoxia, including neuropsychological aspects and genetic determinants related to it.
Dr. Khan praised the study as a “remarkable effort” by Dr. Bhattacharya that creates the road map using a programmatic and translational approach based on a major new finding in the field of neurosciences at Wayne State University.