- Bhanu Jena, Ph.D.
- Jan 12, 2016
A groundbreaking discovery at the Wayne State University School of Medicine into the fundamental mechanism of insulin secretion – critical to the management and treatment of diabetes – could lead to better drug targets for the more than 350 million people worldwide who live with the metabolic disorder.
George E. Palade University Professor and Distinguished Professor of Physiology Bhanu Jena, Ph.D., led a team that showed, for the first time, that isolated insulin-secreting porosomes are functionally reconstituted into live-insulin-secreting beta cells.
“This is huge progress in the field of beta cell biology, insulin secretion and diabetes, given that specific proteins composing the insulin-secreting porosome complex are potential drug targets,” Dr. Jena said.
“Functional reconstitution of the insulin-secreting porosome complex in live cells,” published in the journal Endocrinology, illustrates the clinical importance of the porosome complex discovered nearly 20 years ago in the Jena laboratory.
Secretion is a fundamental cellular process that occurs in all living organisms. Cell secretion is responsible for numerous activities, including neurotransmission and the release of hormones and digestive enzymes.
“We are delighted that after nearly 12 years of background work, we were finally able to functionally reconstitute the porosome complex in live cells. This is a milestone for us,” he said. “We hope to similarly accomplish reconstituting the neuronal porosome complex in neurons and the CFTR-associated porosome complex in the human airways epithelia. These studies, in addition to contributing to our understanding of the molecular mechanism of cell secretion, have promise for drug development therapy. Much work, however, remains to be done.”
An editorial touting the work outlined in the Endocrinology article was published Dec. 4 in the Discoveries journal, a publication of Harvard University.
“The discovery of the porosome complex has come full circle: from elucidation of its structure and dynamics in secretory cells examined, to its structural and functional reconstitution into artificial lipid membranes and secretory cells, and the identification of its important participation in health and disease, resulting in a paradigm-shift in our understanding of the secretory process,” said Iowa State University’s Lloyd Anderson, Ph.D., who wrote the editorial.
Work in the Endocrinology journal article was supported in part by grants from the National Science Foundation, the WSU Interdisciplinary Biomedical Systems Fellowship and the Thomas C. Rumble University Graduate Fellowship.
Additional studies demonstrate the involvement of porosome-associated proteins in neurotransmission and neurological disorders, including Cystic Fibrosis and Post Traumatic Stress Disorder, Dr. Jena said.
“PTSD attributed to traumatic life experiences, explosions or continuous loud white noise pollution has been demonstrated to result in memory loss anxiety and severe sleep disorders, among other health detriments,” Dr. Jena added. “PTSD is shattering the lives of thousands of soldiers returning from active duty, and millions of our civilian population, exposed to PTSD-inducing high amplitude white noise.”
He will lecture on the role of porosomes in PTSD at the Science and Society Conference Feb. 26 at California Institute of Technology in Pasadena, Calif., and will deliver a weeklong series of Distinguished Lectures on the subject at Jawaharlal Nehru University, New Delhi, in June. Both appearances are by invitation, with the India appearance financially supported by the India government’s Global Initiative of Academic Networks.
- Sandeep Sood, M.D.
- Dec 11, 2015
The pioneering surgical technique by Sandeep Sood, M.D., associate professor of Neurosurgery and a neurosurgeon for the Detroit Medical Center’s Children’s Hospital of Michigan, will be featured on the cover of the December 2015 issue of the Journal of Neurosurgery Pediatrics. The minimally-invasive surgical breakthrough could become the standard of care for stopping seizures in patients considered candidates for corpus callosotomy, the structure of nerve fibers that allows for communication between the two sides of the brain, and hemispherotomy. The treatment reduces or eliminates the need for large skull incisions and accompanying risks, including pain, infection, need for blood transfusions and lengthy hospital stays.
“Our method of attaching an instrument to the endoscope is a paradigm shift in minimally invasive brain surgery. Recent addition of 3D endoscope to this technique has provided better lighting, greater magnification and adds precision to the tissue disconnection procedures,” Dr. Sood explained at an International Society for Pediatric Neurosurgery meeting last month in Turkey. “As one of the premier Comprehensive Epilepsy Surgery Centers in the nation, we have extensive experience treating children with intractable seizures. It seemed only reasonable to adapt the endoscopic surgical techniques that we have effectively used in removing brain tumors to epilepsy surgery. We can now safely perform these operations with an incision just about an inch long.”
The article in the Journal of Neurosurgery Pediatrics, published on line, (Endoscopic corpus callosotomy and hemispherotomy, http://thejns.org/doi/abs/10.3171/2015.5.PEDS1531), concluded that “endoscopic disconnective procedures are an attractive option to an open operation.”
The study noted that corpus callosotomy and hemispherotomy have “long been effective in controlling intractable seizures by ‘disconnecting’ the area of the brain where the seizures originate from the normal functioning brain. In the past, however, the procedure required large skull-opening surgery, significant blood loss and a prolonged post-operative course. The new endoscopic version will allow neurosurgeons to enter the skull through a much smaller (2.5 to 3 centimeters) incision, faster healing time, less pain and a shorter hospital stay,” said Steven Ham, D.O., the Peter Schotanus Endowed Professor for Pediatric Neurosurgery for WSU and chief of Pediatric Neurosurgery at Children’s Hospital of Michigan. “This work is pioneering and the result of thoughtful innovation.”
Children’s Hospital of Michigan Surgeon-in-Chief Joseph Lelli, M.D., said the breakthrough is “a significant treatment advance for pediatric neurosurgery and is particularly encouraging for clinicians everywhere who treat intractable epileptic seizures in children.”
“Dr. Sood’s many years of surgical experience and clinical research in finding better therapies for childhood epilepsy were a key factor in the breakthrough,” he added. “They also serve to underline our passionate commitment to clinical research as a crucially important element in our continuing effort to improve patient care at the Children’s Hospital of Michigan.”
- Prashant Mahajan, M.D.
- Sep 23, 2015
Prashant Mahajan, M.D., professor of Pediatrics and Emergency Medicine, and chief of the Division of Emergency Medicine in the Department of Pediatrics at Wayne State University and Children’s Hospital of Michigan, has been awarded a five-year, $5.76 million grant (1R01HD085233) by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. Dr. Mahajan and his collaborators will study how febrile infants – babies 2 months or younger who are brought to emergency rooms with invasive bacterial infections – can avoid invasive procedures such as lumbar punctures, overuse of antibiotics and unnecessary hospitalizations through a new, rapid and more accurate testing to be developed by their research team.
The researchers will investigate whole genome RNA expression profiles to define RNA biosignatures that allow precise diagnosis of isolated bacterial infections, isolated viral infections and bacterial-viral co-infections. The investigators will also validate the RNA biosignatures on a novel PCR-based platform that has a rapid turnaround time of two to four hours, as opposed to current methods of bacterial cultures that often take up to 48 hours for results.
The evaluation of well-appearing febrile infants continues to be challenging and controversial for clinicians. Their immune systems are immature, and even otherwise normal infants are unable to protect themselves from invasive bacterial diseases such as meningitis, bacteremia and urinary tract infections. Fever is the most common reason for infants to be brought to emergency departments and approximately 250,000 very young febrile infants are taken to emergency rooms across the United States annually. In addition, many more are brought to pediatricians and other health care settings.
Dr. Mahajan said that less than 5 percent of febrile infants will have an invasive or serious bacterial illness. These infants are clinically indistinguishable from the majority of the febrile infants with non-bacterial illness. However, the outcomes, such as bacterial meningitis, severe sepsis and potentially death, are devastating. More importantly, the current standard use of bacterial cultures for diagnosis is suboptimal. In particular, culture results reported after 24 to 48 hours are not helpful for clinical decision-making at the patient’s bedside.
Dr. Mahajan and his collaborators, Octavio Ramilo, M.D., of Nationwide Children’s Hospital, The Ohio State University, and Nathan Kuppermann, M.D., M.P.H., of the University of California, Davis Medical Center, have been researching the evaluation of the febrile infant for 15 years and have been continuously funded in their efforts since 2008. The investigative team initially received a $600,000 Targeted Issues Grant (H34MC08509) from Heath Resources Services Administration (HRSA) as part of the Emergency Medical Services for Children to create an infrastructure to study febrile infants in U.S. emergency departments through a federally supported network of approximately 20 pediatric emergency departments called Pediatric Emergency Care Applied Research Network. After establishing the infrastructure, Dr. Mahajan and his collaborators were awarded $3.15 million (R01HD062477) from the NICHD to further define and validate the bacterial and non-bacterial biosignatures of febrile infants. Their findings demonstrated that it is possible to identify bacterial infections from non-bacterial infections by RNA biosignatures in emergency departments with 95 percent accuracy.
“This award will aid in the development of a potentially paradigm-shifting approach of a new, more precise, efficient and rapid laboratory diagnostic strategies,” Dr. Mahajan said. “This would allow for a less-invasive, quicker and more accurate cost-effective evaluation of young febrile infants while bringing this exciting technology to patient’s bedside. If successful, it will substantially impact the care of thousands of febrile infants across the world.”
"Dr. Mahajan's research is highly timely and translational in nature in that it will allow for greater accuracy and enhance antibiotic stewardship among the most vulnerable of all children, very young infants," said Steven E. Lipshultz, M.D., chair of Pediatrics at Wayne State University’s School of Medicine and pediatrician-in-chief of Children's Hospital of Michigan.
“Dr. Mahajan’s research offers much promise to very sick infants, their parents and health care professionals,” said Gloria Heppner, Ph.D., associate vice president for Research at Wayne State University. “His work will assist in quickly and accurately diagnosing them, and ultimately will aid in determining the best treatment method, with potentially lower costs and better results.”
- Stephen Krawetz, Ph.D.
- Jul 21, 2015
A Wayne State University School of Medicine professor, in collaboration with researchers at CReAte Fertility Center, University of Toronto, Harvard University and Georgia Reagents University, has developed the first diagnostic test for sperm RNA based on next-generation sequencing. For couples with unexplained infertility, the test may help determine the best infertility treatment for couples having difficulty conceiving.
Published recently in Science Translational Medicine, “Absence of sperm RNA elements correlates with idiopathic male infertility,” by the laboratory of Stephen Krawetz, Ph.D., associate director of the C.S. Mott Center for Human Growth and Development and the Charlotte B. Failing Professor of Fetal Therapy and Diagnosis in the WSU Department of Obstetrics and Gynecology – with Dr. Meritxell Jodar, Edward Sendler, Robert Goodrich, Dr. Clifford Librach, Dr. Sergey Moskovtsev and Sonja Swanson of CreATe Fertility Center, University of Toronto; Dr. Russ Hauser of Harvard University and Dr. Michael Diamond of Georgia Regents University -- details how male factors could be the cause of infertility in couples even when tested semen parameters are normal. The use of next-generation sequencing of spermatozoal ribonucleic acids, or RNAs, can provide an objective measure of the paternal contribution, and may help guide couples to the most effective method in overcoming infertility.
“Upon validation, this discovery may help to identify those couples who may benefit from assisted reproductive technologies and those couples who may be successful with minimal intervention,” said Dr. Krawetz, also a professor of Molecular Medicine and Genetics. “It is our goal to use this technology to reduce both the time to live birth of a healthy child and the cost when couples seek infertility treatment, so as to reduce the stress on the couple. It is our hope that by identifying the extent of the father’s contribution, the responsibility for setting the course for the birth of a healthy child can now be more equally shared.”
These new findings hold the possibility of dramatic changes in the way infertile couples are treated and assisted in achieving pregnancy. About 13 percent of couples of reproductive age experience fertility problems. While the American Society for Reproductive Medicine estimates that male and female factors contribute about equally to infertility, extensive evaluation of the female partner is traditional before undergoing fertility treatments. Evaluation of the male partner is not as extensive, and is generally relegated to a review of reproductive history, family history and semen analysis considering parameters that include sperm concentration, motility and morphology. The semen parameters evaluation may be useful in the diagnosis of obvious cases of male infertility, Dr. Krawetz said, but no single parameter or set of parameters serve as highly predictive of male fertility. Results of those tests are limited in helping select the least invasive fertility treatment for couples having difficulty conceiving.
The diagnostic potential of next-generation sequencing of spermatozoal RNA indicates this method is “better suited to the task” of analyzing the male’s role in infertility, and is a step toward personalized precision reproductive medicine that may help guide the couple to their successful treatment, Dr. Krawetz said.
Sperm RNA analysis at present is technically challenging, but it is being automated. The technique could become part of a routine examination as “we move toward personalized and precision medicine,” Dr. Krawetz said. While the test is experimental, it has the potential for cost savings for both the patients and the health care system.
The next step is to expand to a prospective blinded study and to begin to define a set of markers that may be predictive of assisted reproduction outcomes.
- Sascha Drewlo, Ph.D.
- Jul 7, 2015
Sascha Drewlo, Ph.D., assistant professor of Obstetrics and Gynecology for the Wayne State University School of Medicine, has secured a $1.25 million grant from the National Heart, Lung and Blood Institute to study the role of approved drugs to improve placental function.
The R01 grant (1R01HL128628) will fund Dr. Drewlo’s research into the effectiveness of the drug rosiglitazone, sold as the diabetic medication Avandia, in stimulating a placental signaling channel to halt severe preeclampsia.
Dr. Drewlo is exploring a novel signaling pathway within the placenta that, when altered with rosiglitazone can restore normal vascular function, preventing preeclampsia in pregnant mothers.
Preeclampsia, a sudden increase in blood pressure after the 20th week of pregnancy, is the leading cause of fetal and maternal death worldwide. Women not killed by preeclampsia can suffer lifelong health problems from the condition. 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 annually, according to estimates from the Preeclampsia Foundation. The condition occurs only during pregnancy. Some mothers develop seizures (eclampsia) and suffer intracranial hemorrhage, the main cause of death in those who develop the disorder. The babies of preeclamptic mothers may develop intrauterine growth restriction or die in utero.
Severe preeclampsia, Dr. Drewlo explained, is believed to stem from the placenta since the only available “cure” is delivery of the fetus. In severe cases, early fetal delivery is necessary, leading to preterm birth, which carries a host of long-term complications for the infant.
At the molecular level, Peroxisome proliferator-activated receptor-gamma, or PPAR-γ, a transcription factor and a nuclear receptor, is primarily known for its role in lipid metabolism. Researchers have shown that PPAR-γ also regulates lineage differentiation in trophoblast stem cells in mice through the control of glial cell missing-1, or GCM-1, a protein-coding gene in the placenta. The trophoblast stem cells provide nutrients to the embryo and develop into a large portion of the placenta. The expression of GCM-1 has been shown to affect the formation of new blood vessels in embryos, which can result in preeclampsia.
Dr. Drewlo has found that when PPAR-γ in placental development in mice was stimulated by rosiglitazone, preeclampsia-like symptoms were reduced. At the same time, inhibiting PPAR-γ induced preeclampsia-like features. Rosiglitazone, when used in diabetics, binds PPAR receptors in fat cells, making them more responsive to insulin.
“We hypothesize that human trophoblast differentiation is regulated by the PPARγ – GCM1 axis, which can be pharmacologically activated to improve placental and, in turn, maternal endothelial function,” Dr. Drewlo said. “The ultimate goal of the proposed research program is to improve pregnancy outcome by restoring placental and maternal vascular function in severe preeclampsia.”
Dr. Drewlo said that in pregnancy, PPAR-γ oversees the release of factors that inhibit the growth of new blood vessels through a GCM-1-dependent pathway. Preliminary studies in human placental explants suggest that PPAR-γ directly controls trophoblast differentiation by regulating the expression of GCM-1. PPAR-γ activation with rosiglitazone significantly decreased the secretion of blood vessel growth inhibitors.
According to the Preeclampsia Foundation, the condition, also known as toxemia or pregnancy-induced hypertension, affects 5 percent to 8 percent of pregnancies. 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 condition can cause blindness in some mothers.
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.
- Lobelia Samavati, M.D.
- Apr 8, 2015
Researchers at the Wayne State University School of Medicine have developed a novel screening tool that can differentiate between sarcoidosis and tuberculosis antigens and that could lead to earlier reliable diagnosis and treatment of both diseases. It may also aid in the development or evaluation of a tuberculosis vaccine.
The non-invasive technique is now pending patent and answers the need to develop accurate tests to diagnose sarcoidosis and TB reliably and quickly.
“We show for the first time that immuno-screening of a library derived from sarcoidosis tissue, which we developed at Wayne State in Detroit, can differentiate between sarcoidosis and tuberculosis antigens. These results are extremely exciting and we believe these findings can revolutionize the fields of both TB and sarcoidosis,” said study principal investigator Lobelia Samavati, M.D., associate professor of medicine and of molecular medicine and genetics, and director of the Division of Pulmonary, Critical Care and Sleep Medicine’s Center for Sarcoidosis and Interstitial Lung Diseases. “We would like to thank the patients and the community for support and encouragement throughout the process of this study.”
The scientists spent two years developing the sarcoidosis library and two years completing the study. Study participants were from the Detroit area. A practicing physician, Dr. Samavati sees patients with lung diseases, especially sarcoidosis, at Wayne State University Physician Group Internal Medicine clinics in Detroit.
“Sarcoidosis is an inflammatory granulomatous disease of unknown etiology affecting multiple organs, and is highly prevalent in Michigan and especially in Detroit. It affects younger adults, especially African-Americans, and can lead to severe morbidity and mortality,” Dr. Samavati said.
The condition strikes between 20 and 50 of every 100,000 Americans annually, most of them between the ages of 20 and 40. Sarcoidosis attacks African-Americans at least 10 times more often than Caucasians, and women more often than men.
Common symptoms include chest pain, a dry cough and shortness of breath. Researchers have not yet identified a cause or a cure for sarcoidosis, an inflammatory disorder of unknown origin. The condition, which manifests as abnormal clumps of immune cells called granulomas, can affect a number of organs such as lungs, brain, eyes and the skin. In some cases, the condition can go into remission without treatment. Extreme cases can require a heart or lung transplant.
Sarcoidosis is most frequently treated with steroids or other immune suppressive medications. According to the National Heart, Lung and Blood Institute of the National Institutes of Health, many patients recover with few or no long-term problems. More than half experience remission within three years of being diagnosed, but the disease can reappear or lead to slow and progressive lung damage requiring lung transplantation. Organ damage occurs in about one-third of patients. While rarely fatal, death from sarcoidosis is generally caused by advanced lung disease, heart failure or brain damage.
Physicians can only use invasive procedures such as tissue biopsy to diagnose sarcoidosis.
Tuberculosis remains a major global health problem. The World Health Organization estimates that more than one-third of the global population is infected with and/or carries M. tuberculosis, or Mtb, a typically dormant infection. Those infected are asymptomatic and non-contagious.
Five percent to 10 percent of latent Mtb carriers will develop active TB, Dr. Samavati said.
“Therefore, it is important to appropriately diagnose and treat both latent TB infection and active TB disease, as well as to discriminate between non-infectious granulomatous such as sarcoidosis and TB. It is not only locally important but also it is important to control the level of contagion in the environment, and ultimately the health of the global population,” she said. “Current available tests have low yield, especially in developing countries. The current mode of detection and diagnosis of Mtb is generally confirmed through a combination of three different diagnostic tools, such as tuberculin skin test, blood-based interferon-gamma or release assays, or IGRA. Most importantly, to diagnose active disease patients need to have a positive sputum culture to confirm Mtb infection. However, generally this gold standard diagnostic test takes about six weeks to get culture results back. This may lead to late diagnosis, late treatment and spreading of the bacteria.”
Dr. Samavati and team outline their method in “Development of a T7 Phage Display Library to Detect Sarcoidosis and Tuberculosis by a Panel of Novel Antigens,” an open-access article published in March in EBioMedicine, a new journal affiliated with The Lancet and Cell.
The scientists have now contacted the WHO to obtain a large collection of sera from patients with tuberculosis and those with latent TB from various countries.
“Future goals involve the validation of these markers on a larger number of sarcoidosis subjects. Additionally, we will apply our novel technology to test whether we can reliably discriminate between the latent TB and active TB subjects sera that we obtained recently from the WHO,” she said.
Dr. Samavati’s research lab is located in the School of Medicine’s interdisciplinary Center for Molecular Medicine and Genetics, built around modern molecular genetics, and comprising basic researchers, physician-scientists, computational scientists and genetic counselors to increase the understanding, diagnosis, treatment and prevention of human disease. Her research team included Department of Medicine Research Associates Harvinder Talwar, Ph.D., who contributed to the study design and sample processing, and Rita Rosati, Ph.D., who developed the T7 phage library and participated in the initial study design, Henry Ford Health System Department of Public Health Sciences’ biostatistician Jia Li, Ph.D., who contributed to data preprocessing and statistical analysis; Samiran Ghosh, Ph.D., assistant professor of Biostatistics, Family Medicine and Public Health Sciences; who contributed to data processing and statistical analysis; and Félix Fernández–Madrid, M.D., Ph.D., professor of Internal Medicine, who contributed to study design and data analysis.
The work is supported by a grant from the National Heart, Lung, and Blood Institute (R21 HL104481). The provisional patent includes the methods and technique to diagnose sarcoidosis in a subject and the markers that can distinguish a sarcoidosis subject from a healthy subject and/or a subject having tuberculosis.