Dr. Ghadimi Earns Mentored Research Award

Kamrouz Ghadimi, MDDuke Anesthesiology’s Kamrouz Ghadimi, MD, has been awarded the 2020 International Anesthesia Research Society (IARS) Mentored Research Award ($175,000, two-year grant) to study “Right Ventricular Metabolic Dysregulation after Surgery for Heart Failure.”

Perioperative right heart failure (RHF) is the leading cause of death within 30 days of left ventricular assist device and heart transplant operations. The objective of Ghadimi’s research is to identify cardiometabolic pathways that underlie early RHF after these operations due to changes in right ventricular (RV) afterload and heterogeneity in response to inhaled pulmonary vasodilators (iPVD). Supported by preliminary metabolomic analyses, the central hypothesis posits that RV-pulmonary arterial (PA) coupling is optimized in the responder phenotype, which signals efficient fatty acid oxidation in RV myocardium. Study aims include 1) quantifying differences in key metabolites using targeted mass spectrometry in serial plasma and RV myocardial samples to determine cardiometabolic pathways, including dysregulated fatty acid oxidation, that underlie early RHF and heterogeneity in response to iPVD, and 2) identifying baseline biomarkers reflecting fatty acid oxidation defects that are associated with RV-PA coupling status, iPVD response phenotypes, and early RHF development to create an integrated clinical-molecular model for outcome prediction in critically-ill patients.

The foundation for this mentored research training grant is embedded in the INSPIRE-FLO clinical trial that Ghadimi has led since 2017 and the biospecimen repository that derived from trial patients undergoing advanced heart failure surgery, such as left ventricular assist device insertion and heart transplantation. As part of this award, Ghadimi and his research team plan to enroll patients undergoing routine cardiac operations by utilizing the vast resources available through Duke Anesthesiology’s Clinical Research Unit. As a member of the Shah laboratory at the Duke Molecular Physiology Institute, Ghadimi is being mentored by laboratory principal investigator (PI) and associate dean of genomics, Dr. Svati Shah, to accomplish the aims of this investigation and to acquire the necessary experiential training to become an independent clinical and translational investigator. As a previous recipient of the NIH T32 award (sponsored by the National Institutes of General Medical Sciences, PI: David Warner, MD), Ghadimi will obtain a Master in Health Science (MHSc) from the NIH-Duke Clinical Research Training Program and pursue additional coursework in precision medicine during this award.

“Receiving this grant is the next step in achieving my long-term goal of using translational methods to identify molecular pathways of right heart failure that will lead to potential novel therapeutic strategies and biomarker discovery for personalized patient care,” says Ghadimi, associate professor of anesthesiology and critical care. “With a large sense of gratitude, being named an award recipient has helped validate (1) the countless hours of hard work and sacrifice that were required to mature this project with my group of mentors and advisors, (2) the time my research team and I have utilized to coordinate multiple resources at Duke that are essential for proper acquisition and storage of biospecimens associated with our parent clinical trial, INSPIRE-FLO, and (3) the importance of ongoing professional development through enrollment in formal research training.”

Stacey HiltonDr. Ghadimi Earns Mentored Research Award
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Dr. Terrando Awarded Grant for COVID-19 Related Research

Niccolò Terrando, BSc (hons), DIC, PhDThe National Institutes of Health has awarded Duke Anesthesiology’s Niccolò Terrando, BSc, DIC, PhD, a one-year, $322,620 supplement grant to his R01-funded project, titled “Delirium Superimposed on Dementia Intersects with COVID-19.”

Delirium has become a common complication of COVID-19 that further impairs the recovery of already debilitated patients, in particular older adults. Terrando and his co-investigators are studying the role of neuroinflammation as a putative driver of delirium pathogenesis. For this supplement, they will explore how lung injury, akin to COVID-19 infection, leads to delirium by impairing the blood-brain barrier and triggering immune cell trafficking into the brain.

Terrando aims to develop a model of COVID-19 lung injury that activates the immune system to damage the brain, affecting areas that serve attention, memory, and thinking, and reverse these changes with an experimental drug in development. Findings from this research supplement will address this serious public health concern by providing fundamental knowledge on the pathogenesis of delirium following COVID-19-like infection. Such work has the potential to reduce the health care burden of COVID-19 associated with delirium and related neurologic complications, such as Alzheimer’s disease and related dementias (ADRDs).

“We are thrilled to develop this project in collaboration with Dr. Purushothama Rao Tata in the Duke Department of Cell Biology, an expert in murine lung injury models, and Dr. Harris A. Gelbard in the Center for Neurotherapeutics Discovery at the University of Rochester Medical Center that developed new therapeutics effective in resolving neuroinflammation, which we are currently testing in the R01 funded project,” says Terrando, associate professor in anesthesiology. “We are grateful for the National Institute on Aging’s continuous support, and we are looking forward to providing timely results that may curtail pathologic hallmarks of delirium and neurodegeneration resulting from COVID-19.”

Stacey HiltonDr. Terrando Awarded Grant for COVID-19 Related Research
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Dr. Devinney Receives Research Award

Michael Devinney, MDThe Society for Neuroscience in Anesthesiology and Critical Care (SNACC) has selected Duke Anesthesiology’s Michael Devinney, MD, PhD, as the 2020 recipient of its William L. Young Neuroscience Research Award for his project, titled “The Association of Blood-Brain Barrier Breakdown with Sleep Apnea and Postoperative Delirium.”

Using pre- and postoperative cerebrospinal fluid samples from the ongoing Sleep Apnea, Neuroinflammation, and cognitive Dysfunction Manifesting After Non-cardiac surgery (SANDMAN) study, Devinney and his co-investigators will determine whether blood-brain barrier breakdown occurs at higher levels in patients with sleep apnea, and whether increased postoperative blood-brain barrier breakdown is associated with worse postoperative delirium. As part of the SNACC award, Devinney will receive $5,000 to be applied toward research expenses for his winning project.

“I am honored to receive the 2020 William L. Young Neuroscience Research Award and grateful for the support from the Society for Neuroscience in Anesthesiology and Critical Care,” says Devinney, assistant professor of anesthesiology. “Also, I am very thankful for the excellent mentorship that I have received at Duke, the support of the Department of Anesthesiology, and the help we have received from our collaborators.”

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Duke Anesthesiology Awarded Program Project Grant

The National Institutes of Health (NIH) has awarded Duke Anesthesiology a five-year, $8,566,593 million Center of Excellence award that is supported via the NIH’s Program Project Grant (PPG) mechanism. This is of substantial significance to the department and university because it marks the funding of a new national center and represents the first PPG to the department in 40 years.

The designation as a Center of Excellence within Duke Anesthesiology’s Center for Translational Pain Medicine (CTPM) by the National Center for Complementary and Integrative Health (NCCIH) brings this department both national and international recognition; there are only 1-3 Centers of Excellence funded as PPGs by NCCIH in the country. The new center represents a new and unique resource to investigators world-wide who have interest in translational pain research; it represents a nidus that not only advances Duke Anesthesiology’s mission in translational pain research, but brings it increased visibility in the pain field, which will further expand international collaboration and increase its value and recognition as a leader in translational pain medicine.

William Maixner, DDS, PhDWe want to sincerely thank everyone who helped drive the Center of Excellence initiative that has resulted in this extraordinary outcome. This award and designation is the culmination of a nearly three-year effort by the CTPM, initiated by the center’s co-directors, including Dr. William Maixner, who worked closely to develop the proposal with the center’s members and affiliates (*see complete list of names below).

The title of the PPG is “Resolution of Neuroinflammation and Persistent Pain by Complementary Approaches.” The overarching aims of the PPG is to identify new and novel complimentary approaches to the treatment of pain conditions. The PPG will support the intellectual development of the Center of Excellence and the infrastructure for three scientific projects and three support cores. These units will further bring together Duke Anesthesiology’s basic science and clinical groups to advance translational pain research.

*P01 collaborators: William Maixner, Shad Smith, Andrey Bortsov, Andrea Nackley, Sven-Eric Jordt, Niccolo Terrando, Luis Ulloa (Anesthesiology), Wolfgang Liedtke and Yong Chen (Anesthesiology and Neurology), Fan Wang (Neurobiology), and Staci Bilbo (Psychology and Neuroscience)

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Postdoctoral Associate Awarded Prestigious Grant

Ravikanth Velagapudi, PhDThe Network for Investigation of Delirium Unifying Scientists (NIDUS) has awarded Duke Anesthesiology’s Ravikanth Velagapudi, PhD, a 2019-2020 NIDUS Junior Investigator Pilot Award (12-month, $80,500 grant) for his proposal titled, “Profiling Postoperative Neuroinflammation in a Mouse Model of Delirium Superimposed on Parkinson’s Disease.”

Velagapudi’s proposal was selected through a rigorous review process from a pool of highly-competitive applications. His project will help gain fundamental knowledge on the impact of surgery on preclinical Parkinson’s disease (PD) models. Currently, millions of Americans live with PD and routinely undergo common surgical procedures, such as orthopedic surgery. Although lifesaving, surgery can increase the risk for cognitive complications like delirium, which in many cases associate with worse prognosis, increased health care costs, and even death. This is especially concerning in frail subjects and older adults who already suffer from ongoing neurodegeneration, such as Alzheimer’s disease, but also PD. This specific project will explore the effects of surgery-induced postoperative neuroinflammation in a genetic PD mouse model. Results from these experiments will provide novel understanding on how surgical trauma synergizes with PD pathology and may lead to novel therapeutic targets to treat delirium in subjects with ongoing PD pathology.

“It is a great opportunity to receive this pilot award from NIDUS under the junior investigator track to study delirium in PD,” says Velagapudi. “To date, this is a largely understudied subject, especially in the context of preclinical models and signaling mechanisms. In fact, few studies so far have addressed the effects of delirium on PD.” This pilot grant also provides a unique and timely opportunity to build a future career development research program for Velagapudi focusing on the interactions between postoperative delirium and PD-neurodegeneration.

Velagapudi is a postdoctoral associate in the Neuroinflammation and Cognitive Outcomes Laboratory in Duke Anesthesiology, led by Dr. Niccolò Terrando, who says this prestigious award is a remarkable accomplishment for his mentee. “I am very proud of Ravi’s achievement in just one year with my team. This award will provide an exceptional training opportunity and will further grow our collaboration with Dr. Laurie Sanders’ group in Duke Neurology, who are experts in PD pathogenesis.”

Velagapudi will present the findings of his project at the annual American Delirium Society meeting in 2021.

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Dr. Warner Awarded NIH Funding to Improve Stroke Outcomes

David S. Warner, MDThe National Institutes of Health’s National Institute of Neurological Disorders and Stroke (NINDS) has awarded Duke Anesthesiology’s David S. Warner, MD, a $475,175, two-year grant for his project, titled “Pharmacologic Suppression of Reperfusion Injury Following Endovascular Thrombectomy in Stroke.”

Ischemic stroke is a leading cause of death and disability in the United States. This often is attributable to thrombus formation at an atherosclerotic plaque or thromboembolism. Patients who present within 4.5 hours of symptom onset are eligible for thrombolysis with tissue plasminogen activator (tPA). This serves less than five percent of victims. Recently, major advance has been made with proven efficacy from endovascular mechanical thrombectomy in combination with tPA. Despite this, less than 50 percent of treated patients have a good recovery.

Basic and clinical science indicate that abrupt restoration of oxygen delivery to ischemic tissue causes reperfusion injury that amplifies/propagates adverse cascades initiated by the initial ischemic insult. There has been widespread call for pharmacologic intervention to mitigate reperfusion injury. The mechanistic basis for reperfusion injury is diverse, but fundamentally associated with rapid onset dysfunction of intracellular mechanisms responsible for regulation of oxygen metabolism. This leads to oxidative stress, inflammation, apoptosis, blood-brain barrier disruption and tissue damage.

Warner and members of his Multidisciplinary Neuroprotection Laboratory are working closely with chemists who have synthesized manganese porphyrins (MnP). MnP have been highly characterized for structure-activity and serve as potent catalytic oxidoreductants. MnP have extraordinary efficacy to favorably modulate redox-mediated activation of transcription factors (e.g., NF-kB, Nrf2) and MAPK and phosphatases. MnP also serve as potent catalytic reductants of reactive oxygen/nitrogen species. They have repeatedly shown enduring improvement in experimental stroke long-term outcome after therapeutic MnP dosing. MnP, now in human trials as a radioprotectant for normal tissue in the context of radiotherapy for brain malignancy, have achieved GMP synthesis, scale-up technology, and requisite preclinical toxicological screening.

Based on highly encouraging pilot data, Warner proposes MnP, given at endovascular thrombectomy reperfusion onset, as an adjunct pharmaceutical to optimize endovascular thrombectomy outcome. In Phase 1, he and his team of investigators will define optimal dosing and maximal ischemia duration before reperfusion and treatment onset that retains efficacy, measure long-term functional outcome in aged, metabolic syndrome, and spontaneously hypertensive rats, define interactions with tPA activity, and obtain independent laboratory efficacy validation. A clinical trial consulting team, consisting of independent stroke experts, will work in collaboration to monitor go/no-go end-points and develop protocols for human dose-escalation trials.

“This project is the preclinical culmination of nearly 15 years of investigation in our laboratory, which was enabled by the discovery of superoxide dismutase at Duke by Irwin Fridovich, PhD,” says Warner, a distinguished professor of anesthesiology. “Dr. Fridovich recently passed away. We are honored to continue his legacy of oxidative stress research by pursuing the very real possibility that these molecules he envisioned and created in collaboration with Ines Batinic-Haberle, PhD, will interrupt degradative enzymatic and transcriptional events initiated by ischemic insults and improve human stroke outcome.  It also is my honor to have worked side by side with Dr. Huaxin Sheng, without whom’s expertise this work would never have happened.”

Stacey HiltonDr. Warner Awarded NIH Funding to Improve Stroke Outcomes
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