Duke Anesthesiology Awarded Program Project Grant

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)

Stacey HiltonDuke Anesthesiology Awarded Program Project Grant
Read More

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.

Stacey HiltonPostdoctoral Associate Awarded Prestigious Grant
Read More

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
Read More

Dr. Nackley Awarded NIH Grant to Study Functional Pain Syndromes

The National Institutes of Health’s National Institute of Neurological Disorders and Stroke has awarded Duke Anesthesiology’s Andrea Nackley, PhD, a $2,623,436, five-year grant for her project, titled “Defining the Role of Peripheral Adrb3 in Chronic Pain and Inflammation.”

Functional pain syndromes affect more than 100 million people, yet remain ineffectively treated because the causes are largely unknown. Accumulating evidence suggests that these syndromes are due, in large part, to low activity of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines. An estimated 66 percent of patients with functional pain syndromes, such as fibromyalgia, possess variants in the COMT gene that lead to low activity of the COMT enzyme. Individuals with the ‘low COMT activity’ genotype report greater pain at baseline and enhanced pain following stressful events that potentiate catecholamine release from sympathetic nerves.

Consistent with clinical syndromes, Nackley’s Translational Pain Research Laboratory has shown that pharmacologic inhibition of COMT in rodents produces pain at multiple body sites and enhances pain following repeated stress. In subsequent studies, they demonstrated that COMT-dependent pain is initiated by peripheral adrenergic receptor beta-3 (Adrb3) through the release of pro-inflammatory cytokines in local tissues. The pain is maintained by subsequent increases in pro-inflammatory cytokines in spinal tissues and activation of mitogen activated protein kinases (MAPKs) in the cell bodies and central terminals of pain-sensing nociceptors. Together, this data reveals that heightened catecholamine tone leads to chronic pain via peripheral Adrb3 and its downstream effectors. However, the cell types that express Adrb3 and mediate pain still need to be identified and the molecular mechanisms determined.

Defining the Role of Peripheral Adrb3 in Chronic Pain and Inflammation

Nackley hypothesizes that activation of Adrb3 on adipocytes (fat cells that surround peripheral nociceptor and sympathetic nerve terminals) drives chronic COMT-dependent pain via increases in cytokines and MAPKs that promote inflammation and nociceptor activation. Further, she hypothesizes that stress-induced catecholamine release amplifies the effects of Adrb3 signaling on inflammation and pain. Preliminary data reveal that COMT-dependent increases in pro-inflammatory cytokines are mediated by Adrb3 located on adipocytes. Additional data reveal that sustained activation of Adrb3 leads to decreased levels of miR-133a, a microRNA expressed in adipocytes that is able to block MAPK signaling. Nackley’s new study will extend this work to directly determine 1) Adrb3 and miR-133a expression patterns in adipose vs other peripheral tissues over time and their relationship to COMT-dependent functional pain, 2) the role of peripheral Adrb3 and miR-133a in mediating COMT-dependent inflammation and neuroinflammation, 3) the role of peripheral Adrb3 and miR-133a in mediating COMT-dependent increases in the activity of mechosensitive and thermosensitive nociceptors, and 4) how these molecular and behavioral phenotypes are influenced by stress.

“Conventional therapies, such as opioids and antidepressants, have poor efficacy for managing chronic pain as well as adverse central side-effects, including altered mental states, addiction, and life-threatening respiratory depression,” says Nackley, associate professor in anesthesiology and faculty in the department’s Center for Translational Pain Medicine. “Results from this study will advance our knowledge about the mechanisms whereby peripheral Adrb3 drives chronic pain and elucidate new targets for the development of peripherally-restricted therapies with improved specificity and side-effect profiles for the treatment of functional pain syndromes.”

Stacey HiltonDr. Nackley Awarded NIH Grant to Study Functional Pain Syndromes
Read More

Introducing the 2020 DREAM Innovation Grant Recipients

2020 DREAM Innovation Grant Recipients

The much anticipated 2020 DREAM Innovation Grant (DIG) recipients were announced at Duke Anesthesiology’s 31st Annual ASA Alumni Event at Lafayette’s Music Room in Orlando on Saturday, October 19th.

Congratulations to the 2020 DIG winners:

DIGs support innovative high-risk and potentially high-reward investigations to accelerate anesthesia and pain management research. Each year, Duke Anesthesiology junior and senior faculty members compete for a DIG by submitting their most innovative research ideas to the DIG Application Review Committee. Dr. William Maixner, vice chair for research, announces the DIG recipients at the department’s annual ASA Alumni Event.

Each DIG recipient can receive up to $30,000 in seed money, which supports their pilot study for one year and ultimately helps them apply for and obtain extramural funding. These grants are funded through a combination of private donors, private companies, alumni, faculty and executive board members. To date, $842,378 has been funded by DIGs, which has led to nearly $15 million in extramural funding to further investigate the role of Alzheimer’s pathways, therapies to improve stroke outcomes, ways to prevent cognitive decline after surgery, blood cell rejuvenation, treatments for obstructive sleep apnea during pregnancy, and more. Click here to view the previous DIG recipients and learn more about their projects.

DIGs are part of the Duke DREAM Campaign, which launched in 2007 to support Duke Anesthesiology’s research programs and initiatives. These grants create an avenue for healthy competition among faculty, inspire ingenuity, promote the careers of young physician investigators, enhance donor communication, and further the department’s academic mission. DIGs help to bridge the gap between training and progression to independent investigator status. Please consider making an online gift to the Duke DREAM Campaign to support our department’s research initiatives focused on improving patient care.

Stacey HiltonIntroducing the 2020 DREAM Innovation Grant Recipients
Read More

Duke Anesthesiology Resident Awarded FAER Grant

Stephan Frangakis, MD, PhD

Stephan Frangakis, MD, PhD

The Foundation for Anesthesia Education and Research (FAER) has awarded Duke Anesthesiology CA-3 resident, Stephan Frangakis, MD, PhD, a Research Fellowship Grant (RFG) for his project, titled “Analgesic Effects of Perioperative Propranolol Administration for Spine Surgery.” RFGs provide anesthesiology residents and fellows with the opportunity to obtain significant training in research techniques and scientific methods. This grant provides $75,000 in funding for Frangakis’ research over one year.

More than 100 million surgical procedures are performed in the United States each year, with up to 80 percent of patients experiencing postsurgical pain. Patients with higher levels of pain after surgery are more likely to develop persistent pain and opioid usage, feeding into a chronic pain epidemic that has a greater annual societal cost than that for cancer, heart disease and diabetes combined. Expanding efforts to identify non-opioid analgesics and adjuncts have yielded promising results and new therapies, yet despite these advances in pain management, there has been little improvement in post-surgical opioid usage and patient-reported analgesia. There remains a significant necessity for the development of novel analgesics, and the co-opting of existing agents for novel uses in the prevention of pain and reduction in opioid consumption.

Frangakis’ proposed study will investigate the postsurgical analgesic and opioid-sparing properties of the non-selective β-blocker propranolol in patients undergoing lumbar fusion surgery. It will also investigate the effects of perioperative propranolol therapy on immune modulation and expression of inflammatory cytokines. The data is expected to demonstrate the utility of perioperative propranolol for reducing pain and opioid consumption after surgery, and elucidate some of these mechanisms.

“I feel very fortunate to be awarded this grant, and for the mentorship and guidance from my mentors, Drs. William Maixner and Thomas Buchheit. I am excited to have this opportunity to carry out this interesting and important research, and to develop my skills as a physician-scientist,” says Frangakis. “I owe a great deal of thanks to many people in the department, including Drs. Joseph Mathew and Dhanesh Gupta, the ACES program, and the anesthesiology residency program. And of course this grant would not have been able to be put together, submitted, and awarded without the contributions from multiple people in the Duke Anesthesiology Clinical Research Unit and the budget office. I look forward to working with everyone involved in the research.”

FAER is a charitable arm of the American Society of Anesthesiologists, dedicated to developing the next generation of physician-scientists in anesthesiology.

Stacey HiltonDuke Anesthesiology Resident Awarded FAER Grant
Read More