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1 OMB No /0002 (Rev. 08/12 Approved Through 8/31/2015) BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FIVE PAGES. NAME: Juan Carlos García Marvizón, Ph.D. era COMMONS USER NAME (credential, e.g., agency login): MARVIZON2 POSITION TITLE: Adjunct Professor EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.) INSTITUTION AND LOCATION DEGREE (if applicable) Completion Date MM/YYYY FIELD OF STUDY Universidad Autónoma de Madrid, Madrid, Spain B.S. 9/1979 Chemistry Universidad Autónoma de Madrid, Madrid, Spain M.S. 12/1979 Biochemistry Universidad Autónoma de Madrid, Madrid, Spain Ph.D. 5/1985 Biochemistry National Institutes of Health, Bethesda, MD postdoctoral Neuroscience A. Personal Statement I am a biochemist with 36 years of experience in neuroscience research, in the settings of industry (two pharmaceutical companies in France), government (NIH and VA) and academia (Autonomous University of Madrid, University of Southern California and UCLA). I have published 57 papers in peer-reviewed journals, being first author of 22 of them and senior author of 20. Since 2000, I have been a Principal Investigator of three R01 grants from the NIH and three Merit Award grants from the VA. I spend 80% of my time doing research, with the rest of the time devoted mostly to administrative tasks closely related to research, like compliance issues and reviewing scientific papers and grants. I have no clinical duties. My teaching duties are limited to training research personnel (postdoctoral fellows and student volunteers) and giving talks related to my research. My scientific career has been in the fields of neuroscience and pharmacology, and could be divided in two phases. From 1981 to 1993 I studied the pharmacology of neurotransmitter receptors: glycine receptors, GABA A receptors and NMDA receptors. From 1994 to the present I worked on pain neurophysiology at UCLA and the VA. At the beginning of this last phase I developed the use of receptor internalization as an in situ measure of neuropeptide release (substance P, opioids and neuropeptide Y) and subsequent receptor activation. I also studied NMDA receptors in primary afferents and their role in neuropeptide release and the induction of hyperalgesia. I have incorporated in my laboratory a variety of techniques to study pain neurophysiology, including spinal cord slice electrophysiology, animal models of neuropathic and inflammatory pain, behavioral pain responses, intrathecal and stereotaxic injections, multiple label fluorescence immunohistochemistry and confocal microscopy. Since 2011 I have worked in close collaboration with Dr. Wendy Walwyn, who contributes her expertise in patch-clamp electrophysiology of dorsal root ganglion neurons and brain slices, as well as in transgenic mice and conditioned place preference and other behavioral models. I also have an ongoing funded collaboration since 2010 with Dr. Bradley Taylor, studying the role of neuropeptide Y and its receptors in the spinal cord in chronic pain. In 2012 Bradley Taylor got me interested in the Latent Sensitization model of chronic pain and we started collaborating in that project as well. Working with my co-investigator Dr. Wenling Chen (a postdoc who stayed in my laboratory as research faculty) and with Dr. Walwyn, we demonstrated that the suppression of hyperalgesia during Latent Sensitization is mediated by µ, δ and κ opioid receptors and α 2A adrenergic receptors, and that at least the µ-opioid receptors are constitutively active instead of being activated by endogenous opioids. We published those findings in January in the Journal of Neuroscience. We also obtained a 4-year grant from the VA to study Latent Sensitization related to neuropathic pain. In this project we proposed to expand our research efforts into the study of the role of stress and descending pain modulation pathways in Latent Sensitization.

2 B. Positions and Honors Positions and Employment Doctoral Fellow, Dept. of Molecular Biology, Universidad Autónoma de Madrid, Madrid, Spain 1982 Student Researcher, Centre de Recherche Delalande, Rueil-Malmaison, France Researcher, Pharmuka Laboratoires, Gennevilliers, France Visiting Scientist - Visiting Associate, Laboratory of Neuroscience, NIDDK, NIH, Bethesda, MD Profesor Titular, Dept. Molecular Biology, Universidad Autónoma de Madrid, Madrid, Spain Research Assistant Professor, University of Southern California, Los Angeles, CA Assistant Researcher, Dept. of Medicine, UCLA, Los Angeles, CA Adjunct Assistant Professor, Dept. of Medicine, UCLA, Los Angeles, CA Adjunct Associate Professor, Dept. of Medicine, UCLA, Los Angeles, CA 2015 present Adjunct Professor, Dept. of Medicine, UCLA, Los Angeles, CA 2007 present Supervisor Research Chemist, VA Greater Los Angeles Healthcare System, Los Angeles, CA Other Experience and Professional Memberships 1991 present Member, Society for Neuroscience 1999 present Member, Brain Research Institute, UCLA 2000 present Member, CURE: Digestive Diseases Research Center 2002 present Member, UCLA Collaborative Centers for Integrative Medicine 2003 present Member, Oppenheimer Family Center for Neurobiology of Resilience and Stress 2010 present Member, International Association for the Study of Pain 2010, 2011 Study Section member, ZDA1 SXC-E (07), CEBRA R21 grants Study Section member, Spinal Cord Injury & Pain, Rehabilitation Research & Development (RRDA), Veterans Health Administration 2011, 2012 Ad hoc member of the Somatosensory and Chemical Senses (SCS) Study Section, Center for Scientific Review, National Institutes of Health Panel member of the Somatosensory and Chemical Senses (SCS) Study Section, Center for Scientific Review, National Institutes of Health. Honors Doctorate Fellowship, Spanish Ministry of Education and Science 1986 Fogarty Fellowship, National Institutes of Health Fulbright Fellowship, Council for International Exchange of Scholars Training Grant, CURE: Digestive Diseases Research Center C. Contribution to Science 1. Substance P release in the spinal cord. Substance P and its neurokinin 1 receptor (NK1R) has long been recognized as key mediators of hyperalgesia in the spinal dorsal horn. In 1995, a seminal paper by Mantyh et al. published in Science showed that NK1R internalization could be used to detect substance P in vivo. I became interested in this technique and proceeded to develop it as a quantitative measure of substance P release both in spinal cord slices and in vivo. I provided a strong validation of this approach by showing that it was more sensitive than conventional immunoassays, while at the same time being non-invasive and providing spatial information on the areas of release. I have published 16 papers using this technique, characterizing the modulation of substance P from primary afferents by NMDA, TRPV1, GABA A, GABA B, µ- opioid, adrenergic α 2A and cannabinoid CB1 receptors. I have also studied the modulation of substance P release by the different firing patterns of primary afferent fibers. Our current work has moved into studying changes in substance P release and its modulation by different receptors during chronic inflammation and neuropathic pain. Studying substance P release is not just valuable because of its direct role in the induction of chronic pain, but also because it provides a window into the functioning of the central terminals of primary afferents. a. Marvizón JCG, Wang X, Matsuka Y, Neubert JK, Spigelman I. Relationship between capsaicinevoked substance P release and NK1 receptor internalization in the dorsal horn. Neuroscience 118: , b. Adelson, DW, L Lao, G Zhang, W Kim and JCG Marvizon. Substance P release and neurokinin 1 receptor activation in the rat spinal cord increases with the firing frequency of C-fibers. Neuroscience 161: , 2009, PMC

3 c. Zhang G, W Chen, L Lao and JCG Marvizon. Cannabinoid CB1 receptor facilitation of substance P release in the rat spinal cord, measured as neurokinin 1 receptor internalization. Eur. J. Neurosci. 31: , 2010, PMC d. Chen W, G Zhang and JCG Marvizon. Src family kinases mediate the inhibition of substance P release in the spinal cord by µ-opioid receptors and GABA-B receptors, but not α 2 adrenergic receptors. Eur. J. Neurosci. 32: , 2010, PMC Opioid release in the spinal cord. The opioid peptides (enkephalins, dynorphins and endorphins) have long been known as key inhibitors of pain in the spinal cord by acting on µ, δ and κ opioid receptors. However, measuring the release of this complex collection of neuropeptides in the dorsal horn has presented a great challenge. By using the internalization of the µ-opioid receptor (MOR) to simultaneously measure opioid release and MOR activation, I was able to describe key mechanisms that control opioid release in the dorsal horn. Thus, we found that opioid release is inhibited by a subpopulation of extrasynaptic NMDA receptors through the opening of K + channels, and also by α 2C adrenergic receptors and by 5-HT 1A serotonin receptors. We also studied the neurons and firing patterns involved in opioid release. Taking our MOR internalization technique in vivo, we studied opioid release in acute and chronic pain conditions. We found that, whereas acute injury and inflammation induce opioid release, there is no sustained opioid release during chronic inflammation. These findings provide important knowledge on the ability of the endogenous opioids to inhibit pain in different conditions. a. Song B, Marvizon JCG. Peptidases prevent -opioid receptor internalization in dorsal horn neurons by endogenously released opioids. J. Neurosci. 23: , 2003, PMC b. Song B, Marvizón JCG. Dorsal horn neurons firing at high frequency, but not primary afferents, release opioid peptides that produce -opioid receptor internalization in the rat spinal cord. J. Neurosci. 23: , 2003, PMC c. Song B, Marvizón JCG. NMDA receptors and large conductance calcium-sensitive potassium channels inhibit the release of opioid peptides that induce -opioid receptor internalization in the rat spinal cord. Neuroscience 136: , 2005, PMC d. Chen, W, and JCG Marvizon. Acute inflammation induces segmental, bilateral, supraspinally mediated opioid release in the rat spinal cord, as measured by µ-opioid receptor internalization. Neuroscience 161: , 2009, PMC Localization and function of neuropeptides and their receptors in the dorsal horn. I have been using immunohistochemistry coupled with confocal microscopy and computer analysis of colocalization to study the localization and function of neuropeptides and receptors in the dorsal horn and the dorsal root ganglion. To complement measures of opioid release, we investigated the types of neurons that express enkephalins and dynorphins in the dorsal horn while establishing that endorphins are not present in the dorsal horn. We also studied the localization of the two molecular components of CGRP receptors: CRLR and RAMP1 and found that they colocalize with opioids and adrenergic α 2C receptors. Indeed, α 2C receptors, together with 5-HT 1A, inhibit opioid release in the dorsal horn. Finally, we have turned out attention to neuropeptide Y (NPY) and its Y1 receptor, adapting our receptor internalization technique to study NPY release in the dorsal horn. a. Marvizon, JCG, W Chen, and N Murphy. Enkephalins, dynorphins and β-endorphin in the rat dorsal horn: an immunofluorescence colocalization study. J. Comp. Neurol. 517: 51-68, 2009, PMC b. Marvizon JC, Perez OA, Song B, Chen W, Bunnett NW, Grady EF, Todd AJ. Calcitonin Receptor-Like Receptor and Receptor Activity Modifying Protein 1 in the rat dorsal horn: localization in glutamatergic presynaptic terminals containing opioids and adrenergic α 2C receptors. Neuroscience 148: , PMC c. Chen W, Song B, Marvizon JC (2008) Inhibition of opioid release in the rat spinal cord by 2C adrenergic receptors. Neuropharmacology 54: PMC d. Taylor BK, Fu W, Kuphal KE, Stiller CO, Winter MK, Chen W, Corder GF, Urban JH, McCarson KE, Marvizon JC Inflammation enhances Y1 receptor signaling, neuropeptide Y-mediated inhibition of hyperalgesia, and substance P release from primary afferent neurons. Neuroscience 256: , PMC Function and modulation of NMDA receptors in primary afferents. NMDA receptors in the spinal cord are one of the most important mediators of hyperalgesia. Some of these NMDA receptors are located in the central terminals of nociceptive primary afferents. I made important contributions to characterizing the function and modulation of these receptors by studying their ability to induce substance P release in the spinal cord. We found that these NMDA receptors are two different diheteromers formed by the association of the NR1 subunit with the NR2B and NR2D subunits, respectively, with the NR2B receptors playing the

4 major functional role at the synapses. More recent work revealed that the function of these NMDA receptors is increased by tyrosine phosphorylation of the NR2B subunit by a Src family kinase. BDNF also increases the function of these NMDA receptors, probably through the same mechanism. This is critically important because these NMDA receptors appear to be dormant in normal conditions and become active when BDNF is released after nerve injury, initiating neuropathic pain. We are currently studying the modulation of these NMDA receptors by opioid receptors and how these mechanisms are involved in Latent Sensitization, a long-lasting condition in which NMDA receptor-mediated hyperalgesia is suppressed by opioid receptors. The mechanisms modulating these NMDA receptors are prime targets to develop drugs to treat neuropathic and inflammatory pain. a. Marvizon JCG, Martinez V, Grady EF, Bunnett NW, Mayer EA. Neurokinin 1 receptor internalization in spinal cord slices induced by dorsal root stimulation is mediated by NMDA receptors. J. Neurosci. 17: , b. Marvizón JCG, McRoberts J, Ennes HS, Song B, Wang X, Jinton L, Corneliussen B, Mayer EA. Two NMDA receptors in rat dorsal root ganglia with different subunit composition and localization. J. Comp. Neurol. 446: , c. Chen W, G Zhang and JCG Marvizon. NMDA receptors in primary afferents require phosphorylation by Src family kinases to induce substance P release in the rat spinal cord. Neuroscience 166: , 2010, PMC d. Chen W, Walwyn W, Ennes H, Kim H, McRoberts JA, Marvizon JC. BDNF released during neuropathic pain potentiates NMDA receptors in primary afferent terminals. Eur J Neurosci 39: , PMC Latent Sensitization to pain. Latent Sensitization (LS) is a rodent model of chronic pain that establishes a new paradigm of how pain control mechanisms are altered in chronic pain disorders. This paradigm proposes that the chronic pain state is a departure from normal pain transmission characterized by an enduring state of pain sensitivity that is suppressed by the continuous activation of opioid receptors and other receptors with analgesic effects. Importantly, this suppression of hyperalgesia can be temporarily turned off by stress. Therefore, LS can explain why many chronic pain disorders occur as periods of normalcy punctuated by pain episodes triggered by stress. a. Marvizon, J C, W Walwyn, A Minasyan, W Chen, B K Taylor. Latent sensitization: a model for stresssensitive chronic pain. Curr Protoc Neurosci 71: , PMC b. Walwyn, W, W Chen, H Kim, A Minasyan, H Ennes, J A McRoberts, J C Marvizon. Sustained suppression of hyperalgesia during latent sensitization by µ, δ and κ opioid receptors and α 2A adrenergic receptors - role of constitutive activity. J Neurosci 36: , PMC Complete List of Published Work in MyBibliography: carlos.marvizon.1/bibliograpahy/ /public/?sort=date&direction=descending D. Research Support Ongoing Research Support Merit Review 1I01RX Marvizón (PI) 12/01/ /30/2019 Department of Veteran Affairs (VA), Rehabilitation Research & Development Service Latent Sensitization and Neuropathic Pain The goals of this grant are to investigate the mechanisms of Latent Sensitization and its suppression by opioid and adrenergic receptors in nerve injury models of neuropathic pain. 1 R01 DA Marvizon, McRoberts (PIs) 07/01/12-04/30/17 NIH/NIDA NMDA receptors in primary afferents The goal of this project is to study the role of NMDA receptors present in primary afferent terminals in the spinal cord in the transmission of pain signals, and how this role changes in neuropathic and visceral pain Completed Research Support VA Rehabilitation Merit Review 1I01RX A1 Marvizón (PI) 03/01/ /28/2015

5 Department of Veteran Affairs (VA), Rehabilitation Research & Development Service Neurotransmitter control of substance P release in the spinal cord The goals of this grant are to investigate the modulation of substance P release in the spinal cord by opioid and adrenergic receptors, in relationship with neuropathic pain. 2 R01 NS A1 Bradley Taylor (PI) 2/01/2010-1/31/2015 (NCE) NIH/NINDS Neuropeptidergic Inhibition of Spinal Pain Transmission This study tests the hypotheses that injury leads to long-term changes in spinal neuropeptidergic pain pathways and that agonists at spinal neuropeptide Y receptors will efficaciously treat chronic pain. Role: Investigator. My role was to measure NK1 receptor internalization in the rat spinal cord.