Duke Team Receives Research Incubator Award

The Duke Institute for Brain Sciences (DIBS) has awarded a 2016 DIG receipient, Niccolo Terrando, PhD, and his team of five co-investigators, a $75,000 grant for their project titled, “Bioelectronic Medicine and Cholinergic Regulation of Postoperative Cognitive Dysfunction.”

Millions of individuals in the U.S. undergo surgery every year for medically necessary conditions and are at risk for developing memory impairments, including postoperative delirium and long-lasting postoperative cognitive dysfunction (POCD). Although risk factors, including age, have been identified, the mechanisms underlying surgical effects on cognitive outcomes are unknown. Thus, there is an urgent need to characterize the mechanisms  that lead to memory dysfunction after surgery and to develop safe and effective therapeutic strategies against this potentially devastating complication. The DIBS 2016-2017 Research Incubator Award will explore the potential for bioelectronic medicine as a novel intervention to prevent POCD. Using a clinically-relevant model of orthopedic surgery in mice, the Duke team linked surgical procedures to the development of inflammation in brain regions that are responsible for overall memory function. Previous work revealed that pharmacological activation of a cholinergic anti-inflammatory reflex can mitigate neuroinflammation and POCD in mice.

The project brings together a multidisciplinary group of investigators with diverse, unique, and complementary expertise from three schools within Duke University (School of Medicine, Pratt School of Engineering, and Arts & Sciences), representing four departments (Anesthesiology, Cell Biology, Biomedical Engineering, Psychology and Neuroscience ). Co-investigators include Professor Warren Grill, Professor Christina Williams, Associate Professor Chay Kuo, Assistant Professor Miles Berger and Associate Professor Staci Bilbo. This is set to provide both basic and translational knowledge in the field of perioperative care: from a basic science perspective, it will explore the fundamental relationship between inflammation, cholinergic function, and memory using a clinically relevant model of peripheral surgical trauma; from a translational perspective, this work will provide a novel therapeutic approach to treat POCD without directly disrupting the innate immune responses to trauma.

Chris KeithDuke Team Receives Research Incubator Award
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Grant Awarded to Study High-Risk Transplants

The Duke University School of Medicine has awarded Drs. Mihai Podgoreanu and Quintin Quinones a $10,000 grant for their project titled, “Sequencing Technology for Rapid Detection of Fastidious and Resistant Infectious Agents in the Critically Ill.”

Infectious disease is a major contributor to mortality in critically ill patients, particularly those who are immunosuppressed. The immediate post-transplant population is acutely at risk for infection given the heavy doses of induction immunosuppression needed to prevent allograft rejection. Of all solid organ transplants, lung transplant patients are particularly at risk for infection, as the recipient is frequently colonized with resistant pathogens pre-transplant; after transplant, the graft is continuously exposed to pathogens from the environment.

Drs. Podgoreanu and Quinones’ central hypothesis is that they can rapidly detect and identify infectious microorganisms, and in some cases, determine their antibiotic resistance patterns using nucleic acid amplification and sequencing technology. With this information, they believe they can more rapidly tailor care plans and antimicrobial therapy for our critically ill lung-transplant recipients. The successful completion of this project will establish a potential rapid assay for the detection of fastidious and often multi-drug resistant organism that is highly relevant to the care of post-lung transplant patients in the cardiothoracic intensive care unit. Additional transformational results of using such sequencing diagnostics directly from respiratory specimens include differentiating colonizers versus pathogens, viral from bacterial pathogens, and phenotypic resistance.

Duke University Medical Center is a high-volume transplant center, particularly for heart and lung transplants. A collaboration is now being formed between physician-scientists in the cardiothoracic intensive care unit, infectious disease, and genomic and computational biologists at Duke University. The awarded funds will cover a portion of the cost of sequencing the genomes of the reference panel and developing a genotyping test panel. These services will be provided by the Genome Sequencing and Analysis Shared Resource.

Chris KeithGrant Awarded to Study High-Risk Transplants
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Dr. Zhang Awarded Grant for Proteomics Research

Zhiquang Zhang, PhDThe Duke University School of Medicine has awarded Zhiquan Zhang, PhD, a $10,000 grant for his project titled, “Proteomic Identification of Novel Sirtuin-3 Regulated Pathways in the Treatment of Acute Myocardial Ischemia-Reperfusion.”

Acute myocardial ischemia-reperfusion (IR) injury remains a major cause of morbidity and mortality. According to Dr. Zhang, there are only a few treatments available but they have limited effectiveness. Dr. Zhang has developed a bioactive peptide (ANXA1sp), recognized as an endogenous anti-inflammatory mediator that plays pivotal roles in resolving inflammation. For the first time, his ongoing findings have revealed that this peptide significantly reduces myocardial infarct size in male but not in female wild-type mice. However, the underlying cardioprotective mechanisms/pathways are still unknown; such knowledge is essential for developing preventive and therapeutic strategies.

Proteomic analysis, a valuable tool for identifying novel proteins and pathways, combined with genetic loss-of-function animal models, represent a unique approach for identifying specific targets and key players in pathways involved in myocardial IR injury. Dr. Zhang and his co-investigator, Dr. Qing Ma, are aiming to perform quantitative proteomic analysis of heart mitochondrial proteins and expect to identify novel pathways associated with ANXA1sp-induced cardioprotection. Analysis will be performed at the Duke Proteomics Core facility. They believe their findings will provide important data for future studies.

Chris KeithDr. Zhang Awarded Grant for Proteomics Research
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Grant Could Lead to Medical Breakthrough

Wulf Paschen, PhD, professor of anesthesiology in the Division of Basic Sciences, received a three-year $1,043,439 National Institutes of Health grant (R01) from the National Institute of Neurological Disorders and Stroke (NINDS) for his research project, titled “Effect of Age on Brain Ischemia/Stroke Outcome; Pathways, Mechanisms, and Rescue.” The goal of the project is to develop a novel strategy for neuroprotection, tailored specifically for elderly patients suffering from brain ischemia/stroke, to improve functional recovery. Working with Dr. Paschen on the project are co-investigators Drs. Wei Yang and Huaxin Sheng (Department of Anesthesiology), and Ivan Spasojevic (director of the PK/PD Core Laboratory), and significant contributors Drs. Dave Warner (Department of Anesthesiology) and John Chatham (University of Alabama at Birmingham).

Brain ischemia, induced by cardiac arrest or stroke, is a serious medical condition that affects more than one million people in the United States each year. The high incidence of brain ischemia-induced disability presents a major burden on families and health care systems. Dr. Paschen believe this problem will become even more serious as our population ages because age is the key risk factor for cardiac arrest and ischemic stroke. Thus, there is an urgent need to define the role of age in brain ischemia/stroke outcome in order to develop novel therapeutic strategies tailored for elderly patients.

Brain ischemia/stroke activates a variety of pathological processes that are believed to contribute to outcome. Traditionally, interfering with these pathological pathways has been exploited as therapeutic strategy. However, according to Dr. Paschen, all clinical trials based on this strategy have produced disappointing results. The Paschen group proposes a novel approach to neuroprotection that boosts an endogenous pro-survival pathway.

“Nature has perfected these stress-response pathways over a long period of evolution, and they are highly conserved, implying that they represent optimal strategies to protect cells from damage triggered by stress. Nature’s overarching strategy is to activate protective pathways that facilitate recovery of cellular functions impaired by stress, not to interfere with pathological processes triggered by stress,” says Dr. Paschen. “This suggests that a better strategy for neuroprotection after brain ischemia/stroke may be to boost a pro-survival pathway.”

Based on results recently published by the Paschen group, the project will focus on the unfolded protein response and downstream pathways with particular emphasis on O-linked b-N-acetylglucosamine (O-GlcNAc) modification of proteins, a pro-survival pathway in a variety of stress conditions. “We expect that our novel strategy to neuroprotection, specifically tailored to increase the resistance of aged brains to an ischemic challenge, could be a major breakthrough toward improving outcomes in elderly patients after an ischemic event,” add Dr. Paschen.

His enthusiasm is shared by the NOMD Review Group at NINDS which considered the strengths of the application to include the outstanding laboratory, the exciting potential of stimulating endogenous protective mechanisms to treat stroke rather than inhibiting injury pathways, and the potential use of this treatment post event. The application was, therefore, highly rated (six percentile) in the first submission cycle, and funding will begin in July.

Chris KeithGrant Could Lead to Medical Breakthrough
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Wei Yang, PhD, Awarded AHA Grant

The research committee of the American Heart Association awarded Duke Anesthesiology’s Dr. Wei Yang a two-year, $154,000 research grant for his project titled, “ER Stress Response in Recovery of Brain Function After Cardiac Arrest.” The award, “MAA Winter 2016 Grant-in-Aid,” begins July 1st of 2016.

Cardiac arrest (CA) causes brain ischemia/reperfusion injury upon resuscitation. CA-induced brain damage presents a major burden on families and health care systems. Currently, hypothermia is the only available treatment option for CA patients. There is, therefore, an urgent need to develop novel therapeutic strategies to improve brain recovery after CA, which requires a better understanding of the mechanisms underlying this brain injury. With this two-year award, Dr. Yang will work with Dr. Wulf Paschen and Dr. Huaxin Sheng to dissect the role of the unfolded protein response (UPR) in recovery from CA-induced global brain ischemia, using unique genetically modified mice that were recently generated in his lab. This research has the potential to provide crucial insights into the pathophysiology of brain injury following CA and to lay the groundwork for future translational studies to unraveling brain injury mechanisms in CA patients as basis to develop new strategies for therapeutic interventions.

Chris KeithWei Yang, PhD, Awarded AHA Grant
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Resident Awarded American Heart Association Grant

The research committee of the American Heart Association recently awarded Dr. Nate Waldron, Duke Anesthesiology CA-3 resident, a two-year, $154,000 research grant for his project titled, “Temporary Autonomic Blockade to Prevent Atrial Fibrillation After Cardiac Surgery.”

Postoperative atrial fibrillation is a common complication after cardiac surgery that significantly increases morbidity, length of stay and mortality. With this two-year award, Dr. Waldron hopes to determine the effects of temporary autonomic modulation on incidence and duration of postoperative atrial fibrillation after cardiac surgery. Additionally, he plans to examine the role of regional autonomic modulation in systemic inflammation after cardiac surgery.

The award, “MAA Winter 2016 Mentored Clinical and Population Research Award,” begins July 1st of 2016. The mission of the American Heart Association is to “build healthier lives, free of cardiovascular diseases and stroke.”

Chris KeithResident Awarded American Heart Association Grant
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