DREAM Campaign BluePrint Update

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Dr. Andrey Bortsov - DIG AwardVoltage gated sodium channel isoform 1.7 (Nav1.7) is a major subtype of sodium channel in primary sensory neurons, which plays a crucial role in pain transduction. Previous studies have validated Nav1.7 as a promising drug target for new analgesics development. Recent discovery of an extracellularly accessible and isoform-specific pocket on voltage-sensing domain 4 (VSD4) resulted in an array of Nav1.7 inhibitors (e.g. aryl-sulfonamides) that show good isoform selectivity and high efficacy in vitro and in vivo. Unfortunately, sulfonamides have several drawbacks resulting in unfavorable pharmacokinetic profile and limited clinical efficacy. There is a need to design new Nav1.7 inhibitors that have high selectivity and potency similar to sulfonamide-based compounds but devoid of their drawbacks.

Dr. Andrey Bortsov’s research group, in collaboration with Dr. Ru-Rong Ji, has identified a novel series of Nav1.7-specific small molecule inhibitors, which potently inhibit sodium currents in Nav1.7-expressing cell line. Systemic and intrathecal administration of the lead compound DA-0218 substantially reduced formalin-induced inflammatory and paclitaxel-induced neuropathic pain, as well as acute and chronic itch, in murine models.

With the help of the DIG award, Bortsov and his team are performing lead optimization of DA-0218 to generate preliminary data for future extramural funding applications, with the ultimate goal to develop new non-opioid treatments for pain and itch. Novel selective Nav1.7 inhibitors will help overcome the opioid crisis by reducing opioid exposure of pain patients and avoiding serious side effects associated with prolonged opioid use. This would lead to improved patient care and better quality of life.

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Dr. Katherine Martucci - DIG AwardWhile chronic pain is highly-prevalent and negatively impacts many lives, it remains unclear how the central nervous system (CNS) is altered and contributes to chronic pain. To study chronic pain, Dr. Katherine Martucci uses advanced technology of functional magnetic resonance imaging (fMRI) to investigate CNS activity in the brain and cervical spinal cord.

Spinal cord imaging in humans is critical to the mission of advancing the understanding of chronic pain. Studying the spinal cord in humans is very challenging, and Martucci’s lab is one of only a handful of research sites globally that have pioneered the use of spinal cord fMRI for chronic pain. In 2019, Martucci and her colleagues published the first evidence of imbalanced spinal cord activity at rest in patients with fibromyalgia, a condition of widespread pain. This finding indicates that increased pain and decreased non-painful sensations may be transmitted to the brain in a different way in patients with chronic pain.

The 2020 DIG is assisting Martucci to establish new research that will advance the understanding of human spinal cord activity in patients with chronic pain. She will further investigate the imbalanced spinal cord activity using a combination of imaging techniques and sensory tests. Ultimately, Martucci and her laboratory will use the data obtained through this award to advance the understanding of fibromyalgia and chronic pain.

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Dr. Mary Yurashevich - DIG AwardPersistent pain after cesarean delivery has an incidence as high as 23 percent, while perinatal depression has an incidence of 15 percent nationwide. The economic burden is about $635 billion in the United States alone, not to mention the emotional and social burden that persistent pain and depression can have on the mother, infant and social support network.

Recently, neuroinflammation has emerged as an important mediator of persistent pain with the release of inflammatory cytokines, such as TNF-α, IL-1β, and IL-18 in the central nervous system (CNS) implicated in central sensitization. Furthermore, there is significant overlap in the inflammatory mediators associated with depression and those involved in the pathogenesis of persistent pain, suggesting that neuroinflammation may be a common etiological process. The studies associating neuroinflammation with the development of persistent pain and/or perinatal depression in parturients are limited. Most studies measure plasma cytokine profiles and it is unclear if plasma reflects the CNS neuroinflammation underlying persistent pain and perinatal depression. The objective of Dr. Mary Yurashevich’s study is to identify biomarkers associated with persistent pain and perinatal depression. The central hypothesis is that the peripartum neuroinflammatory cytokine profile is significantly different among women who develop persistent pain and/or perinatal depression, compared to those who do not develop these conditions.

The 2020 DIG will assist Yurashevich to further pursue studies examining the role of biomarkers in predicting persistent pain and peripartum depression in cesarean delivery, which accounts for roughly one-third of the four million annual births in the United States.

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Dr. Michael Devinney - DIG AwardDr. Michael Devinney’s research aims to discover mechanisms underlying postoperative delirium, an acute confusional state that affects up to 40 percent of older surgical patients and is associated with decreased quality of life, cognitive decline and increased mortality. The 2021 DIG is assisting Devinney’s team to uncover delirium mechanisms, by enabling his team to perform unbiased proteomics on cerebrospinal fluid (CSF) obtained after surgery in patients who developed delirium. Unbiased proteomics will allow his team to measure the levels of hundreds of different proteins to identify potential neuro-inflammatory pathways associated with postoperative delirium. One possible neuro-inflammatory pathway that could be activated after surgery and trigger delirium is the complement cascade, because complement activation can result in synaptic phagocytosis by microglia, leading to decreased synaptic connectivity and cognitive deficits. Thus, Devinney hypothesizes that postoperative CSF complement activation is associated with increased postoperative delirium severity. Another pathway potentially involved in postoperative delirium is the coagulation pathway, because surgery activates peripheral coagulation factors that could pass through a disrupted blood-brain barrier which could then cause neuroinflammation. Thus, Devinney also hypothesizes that postoperative CSF coagulation pathway activation is associated with increased postoperative delirium severity. The DIG will allow the establishment of this line of innovative research using unbiased proteomics of postoperative CSF to uncover specific neuro-inflammatory pathways underlying postoperative delirium. This work will provide the groundwork for grant proposals for larger studies aimed at uncovering mechanisms of postoperative delirium that could lead to new drug targets to reduce postoperative delirium and its sequelae.

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Dr. Heath Gasier - DIG AwardAge related decline in muscle mass and obesity, sarcopenic obesity, is characterized by oxidative damage and low-grade inflammation that are linked to impaired mitochondrial quality control and function. Because the heme oxygenase (HO)-1 enzyme system is critical in the cellular antioxidant and anti-inflammatory stress response that is linked to mitochondrial quality control (mitochondrial fusion and fission, mitophgagy and biogenesis), HO-1 induction impairment may be a mechanism for disease progression and increased mortality rates. The objective of this research is to determine whether the skeletal muscle HO-1 enzyme system is impaired in sarcopenic obesity. The central hypothesis is that sarcopenic obesity suppresses stress-induced activation of skeletal muscle HO-1 resulting in increased oxidant production, inflammation, and impaired mitochondrial quality control. Young and old mice will consume a high-fat or control diet for 16 weeks. At the end of the dietary intervention, mice will be exposed to room air or 100 percent oxygen to induce HO-1. Measurements will include skeletal muscle HO-1 mRNA and protein expression, and HO-1 enzyme activity, mitochondrial oxidants and antioxidants, biomarkers of inflammation and anti-inflammation, and mitochondrial quality control. The expected outcome of this work is a basic understanding of whether the HO-1 enzyme system is impaired in sarcopenic obesity. The results will have an important positive impact because they lay the groundwork for testing targeted interventions for preserving skeletal muscle mass and metabolic health in obesity and aging, and reducing mortality in critically ill patients.

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Marie-Louise Meng - DIG AwardPreeclampsia is a hypertensive disorder of pregnancy that is associated with cardiovascular morbidity. The mechanism of this association is unknown. Studies of women with preeclampsia with careful phenotyping, including cardiovascular imaging and biomarkers, are vital to address this knowledge gap. Women with preeclampsia have been shown to have diastolic dysfunction and myocardial strain impairment, but the prevalence and biological underpinnings of this relationship have been incompletely evaluated. Metabolism is at the core of cardiac dysfunction and markers of impaired metabolism are elevated in heart failure, but whether these metabolic processes are also impaired in preeclampsia is unknown.

The DIG is allowing Dr. Marie-Louise Meng to conduct a prospective study that assesses echocardiographic phenotype and measures metabolic markers of myocardial dysfunction as well as candidate preeclampsia and heart failure biomarkers in women with early onset preeclampsia with severe features. The results of this study aim to shed light on the metabolic underpinnings of cardiac dysfunction and related metabolic defects in preeclampsia.

Contents

COVER STORY
Anesthesiologists on the Front Lines of a Pandemic

FEATURE
A Comprehensive Approach to Pain

FACULTY SPOTLIGHT
Dr. Nicole Guinn

INNOVATIVE RESEARCH
Dr. Padma Gulur
Dr. Vijay Krishnamoorthy
Dr. Katherine Martucci

DEPARTMENTAL
Message from the Chair
Full Frame: Run for the Warriors
Departmental Highlights
Departmental Listing
ASA Highlights

DREAM CAMPAIGN
Donor Honor Roll
About DIG
2020-2021 DREAM Innovation
Grant Recipients

GLOBAL HEALTH
Duke Health Sends Supplies to India to Assist with Covid-19 Crisis
Blogs from Abroad

RESIDENCY CORNER
Resident Spotlight
Welcome Match Classes of
2024 and 2025
Alumni Shoutout
New and Noteworthy

Chris KeithDREAM Campaign – BluePrint