Andrea G. Nackley, PhD – 2019

2019 DIG Research Project | “A Molecular Exploration into Comorbid Chronic Pain and Obesity”

Background

Andrea G. Nackley, PhD - 2019 DIG RecipientAndrea Nackley, PhD, is an associate professor within Duke Anesthesiology’s Center for Translational Pain Medicine with a joint appointment in the Department of Pharmacology and Cancer Biology at Duke University. She has a longstanding interest in understanding genetic, biologic and environmental mechanisms that contribute to chronic functional pain disorders and in identifying new therapeutic strategies to improve patients’ pain management and quality of life. Nackley is committed to pain research and education at the local, national and international level. Since joining the faculty at Duke University, she has launched the Duke Pain Journal Club, where basic scientists, clinicians and statisticians get together the first Friday of every month to discuss new cutting-edge research. Nationally, she is an active member of the American Pain Society (APS), where she has served as chair of the Genetics and Pain Special Interest Group, member of the Nominating Committee, and currently serves as the chair of the Early Career Forum. She also remains an active reviewer for the NIH Study Section as well as for nearly 30 journals in her field. In 2010, she received the John C. Liebeskind Early Career Scholar Award from the APS in recognition of her research and scholarly activity in the pain field. Internationally, she is an active member of the Society for Neuroscience and the International Association for the Study of Pain, where she has lectured on topics such as opioid hyperalgesia, microRNA signatures of chronic pelvic pain, and adrenergic contributions to functional pain.

Nackley is originally from Roanoke, Virginia. As an undergraduate, she attended Virginia Polytechnic University, where she majored in psychology and biology. She went on to obtain a doctoral degree in neuroscience from the University of Georgia under the mentorship of Dr. Andrea Hohmann. Nackley then completed a post-doctoral fellowship in the Center for Pain Research and Innovation at the University of North Carolina under the guidance of Drs. William Maixner and Luda Diatchenko. These earlier research experiences in the areas of neuroscience, behavioral pharmacology, molecular biology, and genetics were instrumental to her growth and development as an independent investigator in the field of pain.

In 2006, Nackley joined the faculty at the University of North Carolina as an assistant professor in the Department of Endodontics with a joint appointment in the Department of Pharmacology and an affiliation with the curriculum in Neurobiology. At this time, she received an NIH Roadmap Award, which promotes multidisciplinary clinical research. Through this program, she was able to work alongside prominent clinicians in orofacial, pelvic and headache pain clinics to gain training and experience in human pain phenotyping, clinical exams and clinical epidemiology. Gaining this clinical experience and intelligence evolved the way she thinks about pain and the way she studies pain.

Research

Nackley’s overarching goal is to improve the management of chronic pain by way of research discovery. Our limited understanding of the molecular mechanisms underlying chronic pain is due, in large part, to patient heterogeneity. An individual’s pain experience is as unique as their fingerprint – shaped by many factors, including the context surrounding the event, past experiences, stress level, belief systems, coping strategies, and general health. Combine with that, individual variability in genes that regulate the development and function of the nervous system, immune response, and psychological mood, and one can appreciate the complex nature of pain. This complex problem will only be solved with a complex approach.

Thus, her lab has adopted a translational bedside-to-bench and bench-to-bedside approach to the study of chronic pain conditions. She works with clinicians on large-scale collaborative projects that inform hypotheses tested in basic independent studies, which then inform more advanced clinical studies (eg, clinical trials). By marrying pain neurobiology, behavioral pharmacology and molecular genetics with clinical epidemiology, she aims to bridge the significant gap that exists between basic science and clinical research in order to better understand the mechanisms underlying maladaptive chronic pain conditions and identify more rational treatment strategies.

DREAM Innovation Grants (DIG), made possible through Duke Anesthesiology’s DREAM Campaign, support innovative, high-risk investigations with the potential to significantly accelerate anesthesia and pain management research. Nackley is excited to have received a 2019 DIG to advance her pain research in the context of obesity.

Chronic pain and obesity are prevalent, ineffectively managed health conditions that often co-occur. In the United States, chronic pain and obesity each affect nearly one in three individuals. An estimated 40 percent of obese individuals also suffer from chronic pain conditions, including headaches, low back pain and fibromyalgia. The overlap of chronic pain and obesity has been shown to worsen a patient’s functional status and quality of life, adding to the disability caused by each condition in isolation. While the mechanisms underlying the overlap between chronic pain and obesity remain understudied and unclear, a hallmark feature of both chronic pain and obesity is increased systemic inflammation. Her preliminary data suggest that pain- and obesity-relevant inflammation is driven through adipocyte Adrb3 via miR-133-mediated increases in cytokines, which activate local immune cells. Building on our preliminary data, we propose an innovative set of studies that will identify, for the first time, molecular features of adipose tissue expansion that underlie comorbid chronic pain and obesity. In collaboration with Drs. Keri Seymour and Dana Portenier in the Division of Metabolic and Weight Loss Surgery, they will analyze biological samples (SAT, VAT, and plasma) and clinical data collected from 40 patients undergoing bariatric surgery (N=20 obese with chronic pain, and 20 obese without chronic pain). They will examine 1) levels of cytokines (eg, IL-6) and adipokines (eg, leptin) in adipose and plasma using multiplex assays, 2) infiltration of immune cells (eg, M1-like inflammatory macrophages and T cells) in adipose using immunohistochemistry, 3) gross histological features (eg, hyperplasia vs hypertrophy) of adipose using H&E stain, and 4) expression of Adrb3 and miR-133a in adipose using quantitative PCR. In addition, they will examine the relationship between these molecular markers and quality of life measures (eg, perceived health and mood). The hypothesize that compared to obese individuals without chronic pain, those with chronic pain will have increased levels of cytokines/adipokines in adipocytes and plasma and greater number of inflammatory immune cells in adipose alongside increased expression of Adrb3 and decreased expression of miR-133a in adipocytes. Further, local and systemic inflammation will be positively correlated with poorer physical and mental health.

Results from these studies are expected to serve as preliminary data for an R01 grant application geared towards better understanding mechanisms that drive comorbid chronic pain and obesity and, importantly, identifying biomarkers for patient-centered outcomes following bariatric surgery and new targets for the development of effective treatments for obesity, chronic pain and associated comorbidities.

Chris KeithAndrea G. Nackley, PhD – 2019