Todd W. Vanderah - US grants

DESCRIPTION (provided by applicant): Recent evidence suggests that, in addition to analgesia, opioids produce unexpected, paradoxical pain in both preclinical and clinical settings. In the case of morphine, opioid-induced pain limits not only acute antinociceptive efficacy but also appears to promote the decreased antinociception seen with sustained exposure (i.e., behavioral opioid antinociceptive tolerance). Manipulations which block morphine-induced pain also block the decrease in antinociceptive potency seen with sustained morphine, suggesting that opioid-induced pain may represent an important component of antinociceptive tolerance to this drug. Among the manipulations which block morphine-induced pain and antinociceptive tolerance are rostral ventromedial medulla (RVM) injection of lidocaine and bilateral lesions of the dorsolateral funiculus (DLF) suggesting a tonically active descending pain modulatory (facilitatory) system which maintains morphine-induced pain and antinociceptive tolerance. Whether the observations made with morphine extend to other agonists of differing opioid receptor selectivity is not known. This proposal hypothesizes that morphine enhances cholecystokinin (CCK) release in the RVM which then promotes opioid-induced pain and antinociceptive "tolerance." Supporting this possibility are preliminary data which show that RVM CCK produces "pain" in animals not exposed to opioids which is blocked by DLF lesions. Additionally, acute and sustained morphine increases release of CCK-LI in the RVM. Three aims will test this hypothesis. Aim 1 will investigate the release of CCK-LI in the RVM following acute local or systemic morphine, the time-course of this effect and the opioid receptor mediating this effect. Aim 2 will address the actions of sustained systemic morphine in regulating enhanced RVM CCK-LI release, its time-course and correlation to pain, and the opioid receptor mediating enhancement of RVM CCK-LI release during sustained opioid delivery. Aim 3 determines if an RVM CCK antagonist prevents the development of opioid induced pain and prevents or reverses spinal or systemic opioid antinociceptive tolerance. These studies will determine if opioid-induced release of RVM CCK represents the tonic driving force which maintains morphine- or opioid-induced pain and antinociceptive tolerance. The studies offer new insights into physiological mechanisms of opioid tolerance and strategies which might be employed to prevent opioid-induced pain and antinociceptive tolerance. These approaches may allow for sustained efficacy of morphine or opioids and their use in the treatment of chronic or prolonged pain states.

DESCRIPTION (provided by applicant): My interest in research began as an undergraduate at the University of Arizona (U of A). Since that time I have developed as an independent scientist in the field of pain. Several milestones are noteworthy including the establishment of my laboratory, recruitment of students and a postdoctoral fellow, receiving my first 5 year R01 NIH-NIDA sponsored grant, invitations to speak at national/international meetings and in academic settings, forging new collaborations and continuous publications in peer reviewed journals. These accomplishments have offered a taste of a career in which I hunger for, however my appointment in the Department of Pharmacology came with a significant teaching commitment that, although important tends to abate my time for basic research. If I were to receive this Career Development Award, I would pursue specific research objectives including; 1) Continue to strengthen my primary research program; 2) Develop a new/extended hypothesis for a renewal of the current NIH-R01; 3) Publish; 4) Present my data at national/ international meetings; 5) Collaborate with the group of pain-neuroscientist/ pharmacologists/chemists here at the U of A. My research career goal is to establish an interdisciplinary research program aimed at understanding the mechanisms that drive the activation of supraspinal descending pain facilitatory pathways in the presence of sustained opioids. The ultimate goal of these studies is to understand the neurobiological consequences of sustained opioid administration and to determine the role of these adaptations. This proposal hypothesizes that morphine enhances cholecystokinin (CCK) release in the RVM which then promotes opioid-induced pain and antinociceptive "tolerance". The studies offer new insight into physiological mechanisms of opioid tolerance and strategies which might be employed to prevent opioid-induced pain and antinociceptive tolerance which may allow for the development of novel pain relieving compounds. The U of A has earned recognition as a top Research One University ranked 13th among public universities. The U of A has in place the infrastructure needed to support and oversee research activities including several core research laboratories, interdisciplinary academic programs and large multi-disciplinary center programs. These facilities were put into place to support and promote interdisciplinary collaborations which initiate new research and educational programs of high priority to the scientific community. I have adequate space, equipment, the ability to recruit graduate students from multiple programs, and have access to numerous shared resources. In summary, the U of A and the Department of Pharmacology provide an outstanding environment to promote science and foster career development.

by the Chemistry Core. These compounds will be designed as opioid agonists and bradykinin/dynorphin antagonists in order to produce potent and efficacious antinociception targeting the pathology of neuropathic pain while eliminating antinocicpetive tolerance. The Biochemical Core contains 7 aims that will test such novel compounds. The in vitro pharmacological data in particular will provide timely feedback to the Chemistry Core on the structure-activity relationship (SAR) to further inform chemistry design. The initial binding and functional characterization of all novel compounds (est. 20 to 50 compounds/year) is necessary and essential for target-based drug discovery. To identify lead compounds, we must evaluate their affinity at multiple opioid and bradykinin receptors, and their apparent biological activity at each of these receptors. Studies will include in vitro tissue assaysto determine agonist and antagonist activity as well as novel compound activity at calcium channles using calcium fluorimetric analysis in transfectd cells. We will use a number of in vivo animal models to identify whether such novel bi-functional compounds produce antinociception as well as antihyperalgesia in inflammatory and chronic pain states. Finally, in vivo studies will be performed to detemine whether such compounds will result in antinocicpetive tolerance. Overall, Studies will be performed to identify molecules with agonist activity at one receptor and concurrent antagonist actions at a second receptor. The biochemical core provides dedicated equipment, personnel and expertise in data analysis for the entire project. It serves to centralize the use and maintenance of shared equipment and the technical training of personnel to use these equipment, management and oversight of animal protocols required by IACUC and Radiation Control, as well as to ensure data and information sharing with the Chemistry Core and the other projects. The biochemical core will synergize with projects A, C and D by providing lead compounds to directly test their hypotheses. RELEVANCE (Seeinstructions): Inflammatory and chronic neuropathic pains are growing areas of unmet medical need. Clinically, chronic pain remains poorly controlled by available therapies and thus adversely impacts quality of life (Arner & Meyerson, 1988). One reason for this lack of effect is the absence of compounds that specifically target the pathology of neuropathic pain. The goal of the chemistry & biochemical core of this PPG are to synthesize and test compounds that result in potent and efficacious antinociception while eliminating tolerance. PROJECT/

DESCRIPTION (provided by applicant): Statistics show that 1 out of every 7 females in the US will develop breast cancer in their lifetime, with 75-95% of patients with advanced breast cancer having chronic, excruciating pain associated with metastasis of the cancer to bone. Pain from metastatic breast cancer appears to be simultaneously driven by inflammatory, neuropathic and tumorigenic mechanisms. Such pain is extremely difficult to treat causing quality of life in these patients to be severely compromised. Being able to more fully control bone cancer pain, without the side effects of currently available analgesics, would significantly improve the functional status, quality of life while reducing health care costs in breast cancer patients with skeletal metastases. A major problem in designing new therapies to treat breast cancer-induced bone pain has been the lack of a model available to define the mechanisms that generate and maintain breast cancer induced bone pain. The major thrust of this proposal is to use a mouse model we have recently developed that closely mirrors the bone remodeling and chronic pain often observed in patients with breast cancer- induced bone pain. Mouse 66.1 breast cancer cells, stably transfected with green fluorescent protein, are injected and confined to the intramedullary space of the femur of the non-immunocompromised mice. Over a twenty-one day period, these tumor cells proliferate in the marrow space and induce bone remodeling, bone cancer related pain behaviors and ultimately fracture of the bone. Recent data has suggested that cannabinoid CB2 agonists can provide significant analgesia in a variety of preclinical pain models with a minimal side effect profile. Intriguingly, data from osteoporosis studies have suggested that activation of CB2 receptors is pro-osteogenic (bone-building) and preliminary data from our lab suggests CB2 agonists have direct anti-tumor effects in both mouse and human breast cancer cells. In the present proposal, we will explore the hypothesis that CB2 agonists can have multiple beneficial actions to reduce breast cancer-induced bone pain, reduce tumor induced bone destruction and fracture and reduce the growth of breast cancer cells both in vitro and in vivo. The specific hypotheses to be tested are: CB2 receptor activation will result in antihypersensitivity in a murine model of breast-induced bone cancer pain while lacking the unwanted side effects seen with current analgesic therapies. Experimental studies proposed in this application will: 1) aid in our understanding of the pain relieving effects of the CB2 receptors in breast-induced bone cancer, 2) identify whether CB2 agonists will enhance bone remodeling and reduce bone fracture in a murine model of bone cancer using breast cancer cells, 3) identify whether CB2 agonists inhibit the proliferation of breast cancer cells both in vitro and in vivo, 4) identify whether CB2 receptor activation results in a decrease in pronociceptive factors including IL-12, IL-6, and TNF1, 5) identify whether chronic administration of CB2 agonists in a murine model of bone cancer results in unwanted side effects, and 6) most importantly, offer a novel target for new and innovative therapy for patients suffering from bone cancer due to breast metastases. New treatments are urgently needed that would result in adequate pain relief without the debilitating CNS side effects of current agents, as well as inhibit bone degradation, avoiding painful bone fractures induced by the metastases and result in disease modification. These studies are likely to offer new opportunities for the development of strategies to treat pain resulting from metastasis of breast to bone as well as possible applications to other bone cancers. PUBLIC HEALTH RELEVANCE: Breast cancer is the most frequent malignant tumor in women in North America. With nearly 200,000 women diagnosed each year in the U.S., there is a great need for novel therapeutic intervention in treating breast cancer patients in pain. Breast cancer commonly metastasizes to the bone resulting in excruciating pain, bone remodeling and eventual bone fracture contributing to incapacitating pain and limited or total loss of mobility. The U.S. National Institutes of Health estimate overall costs of cancer in the U.S. in 2006 to be $206.3 billion with $78.2 billion in direct medical costs (Arrowhead Publishers, 2008). Unfortunately, current therapies result in unwanted side effects and even promote further deterioration of the bone and hypersensitivities. This proposal addresses whether CB2 agonist will attenuate breast cancer-induced bone pain without resulting in unwanted side effects seen with current analgesic therapies. CB2 receptors are found on immune cells and on cells that regulate bone mass but not on neurons of the central nervous system. The activation of CB2 receptors with agonists inhibits several inflammatory factors that promote pain, significantly attenuate spontaneous pain due to bone cancer, inhibit the degradation of bone, and reduce breast cancer cell proliferation within the bone. Yet, CB2 agonists do not result in the unwanted side effects such as constipation, somnolence, respiratory depression, analgesic tolerance or rewarding "addiction" effects.

DESCRIPTION (provided by applicant): The World Health Organization estimates that the number of women living with breast cancer globally will rise to 15 million by the year 2020 with a significant portion of these patients in advanced stages of the disease. Breast cancer is the most frequent malignant tumor in women in the U.S. with nearly 200,000 women diagnosed each year. The U.S. NIH estimate overall costs of cancer in the U.S. in 2006 to be $206.3 billion with $78.2 billion in direct medical costs. Breast cancer commonly metastasizes to the bone resulting in excruciating pain, bone remodeling and eventual bone fracture contributing to incapacitating pain and limited or total loss of mobility. A recent study in cancer patients demonstrated a significant and severe deficit in treatment options for cancer pain, with a much higher incidence in minority patients. Reports also highlight the importance of patient quality of life in late stages of cancer, as well as the effects on surrounding family and physicians. Unfortunately, current therapies for cancer-induced bone pain result in unwanted side effects and even promote further deterioration of the bone and hypersensitivities. This application addresses this unmet need by investigating the novel cathepsin inhibitor VBY-825 (Patent WO 2006/102 243) in attenuating breast cancer-induced bone pain and bone resorption without resulting in unwanted side effects seen with current analgesic therapies. The potential for broad application to bone cancer metastases and the associated pain derived from other types of tumors is significant for this potential therapeutic. The cathepsins (11 cysteine protease subtypes) include cathepsins B, S, and K, the three subtypes thought to be involved in bone cancer pain. Cathepsin B is involved in cancer metastasis, initiating the breakdown of connective barriers of the extracellular matrix and basement membrane, thereby allowing cancerous cells to invade new tissues and organ sites by entering the bloodstream. Cathepsin K is selectively expressed in osteoclasts and is essential in osteoclast-mediated bone resorption. Importantly in bone cancer, cathepsin K may also be involved in the formation of osteolytic lesions. Cathepsin S has recently become associated with nociception. Rodents with a partial ligation of the left sciatic nerve (PNL), showed increased expression of cathepsin S in the dorsal horn of the spinal cord. Cathepsin S inhibitors have analgesic efficacy in this model and a number of models of neuropathic pain implicating cathepsin S, as a significant new target for analgesic efficacy in neuropathic and inflammatory pain. Virobay Inc. has developed a spectrum-selective cathepsin inhibitor of K/S/B (CatK, Ki=2.3 nM) (CatS, Ki=130pM) and (CatB, Ki=330pM) for use as a potential therapeutic in oncology with specific utility in the inhibition of bone cancer pain. Here we propose that a spectrum- selective cathepsin inhibitor will result in a significant reduction in spontaneous and evoked pain behaviors in a murine model of breast-induced bone cancer pain while lacking the unwanted side effects seen with current opioid analgesic therapies. Three aims are proposed, including testing of the VBY-825 in a well established murine model of breast-induced bone cancer for efficacy in reducing pain behavior (Aim 1), bone loss, clinically relevant serum markers, and bone mineral density measures (Aim 2), and the pharmacokinetics and pharmacodynamics of VBY-825 with comparisons to current clinical treatments of morphine and the bisphosphonate zoledronic acid (Aim 3). In summary, a significant number of human and murine breast cancers express cathepsins and the investigation of VBY-825 (a spectrum-selective inhibitor of cathepsins K/S/B) may offer a novel therapeutic to many bone cancer patients that suffer from pain, bone loss and the unwanted side effects of current therapies including the very high doses of opioids for pain used in almost all patients.

Abstract: Breast cancer is the most frequent malignant tumor of women of all races in North America and is the second leading cause of death among women (DHHS, CDC, & NCI; 2014) with an overall NIH estimate costs to the U.S. over $200 billion with $88.7 billion in direct medical costs in 2011. The World Health Organization predicts that global cases of cancer will rise to 15 million new cases by 2020. In advanced stages, skeletal metastasis causes incapacitating pain and is prominent in 75?90% of cancer patients. First line therapy to treat bone cancer pain includes mu opioid receptor agonists. Opioids are well known for producing unwanted side effects in cancer patients including severe somnolence, constipation, etc. but recently have been shown (clinical and preclinical) to enhance the risk of bone loss and fracture. In addition, sustained opioids have demonstrated a propensity for increasing proliferation and migration of different cancers including breast cancer. Data from our laboratory, and others, suggest that cannabinoid CB2 agonists may be effective in alleviating bone cancer pain and bone loss. Selective CB2 agonists significantly inhibit bone cancer pain while NOT resulting in the psychotropic or euphoric effects seen with CB1 agonists or narcotics. Recent reports and data from our lab have identified CB2 agonists as significantly reducing self-administration of drugs of abuse including cocaine and narcotics. Increasing endogenous cannabinoids (MAGL inhibition to increase 2- arachidonylglycerol - 2AG) may regulate bone mass, decrease pro-nociceptive factors and act synergistically with morphine to inhibit cancer-induced bone pain (CIBP) and attenuate tumor proliferation. Our preliminary studies using a murine bone cancer model indicate that MAGL inhibition and CB2 receptor activation inhibits proinflammatory cytokines/chemokines via regulating NF-?B. Yet, there is very little known about the endogenous CB2 system in bone cancer pain/inflammation, and whether the activation of the endocannabinoid (eCB) system, while administering mu opioids, will significantly aid bone cancer patients. There are NO studies investigating the synergistic combination of MAGL inhibitor or CB2 agonists with a mu opioid agonist on cancer pain, bone integrity, tumor proliferation, or attenuating mu opioid unwanted side effects. Our progress in characterizing bone cancer pain has resulted in twelve direct peer-reviewed publications and preliminary data to further support studies of MAGL inhibition, CB2 receptor activation in bone cancer pain. Our preliminary data demonstrate; 1) a reproducible syngeneic breast-induced bone cancer model representative of the clinical state, 2) MAGLipase inhibition resulting in increased 2AG, significantly attenuating cancer-induced pain, 3) exogenous and endogenous CB2 agonists attenuating bone loss, 4) sustained morphine alone increases bone degradation and cytokines, 5) CB2 agonists and MAGL inhibitors decrease NF-kB signaling, inhibiting several pro-inflammatory cytokines/chemokines, while reinstating apoptosis in breast cancer cells, 6) synergistic inhibition of CIBP with morphine and CB2 agonists, and 7) CB2 agonists lacking unwanted side effects. Hence, MAGLipase inhibitors in combination with morphine may be synergistic in alleviating bone cancer pain, attenuate breast cancer proliferation while maintaining bone mass. In response to the recent call for proposals (RFA PA-15-188) titled ?Developing the Therapeutic Potential of the Endocannabinoid System for Pain Treatment? and our preliminary findings have led us to hypothesize that MAGLipase inhibition and/or CB2 receptor activation, in combination with a Mu opioid agonist will result in the synergistic inhibition of pain behaviors in a murine model of breast-induced bone cancer pain while attenuating bone loss seen with opioids. Mechanistically, 2AG and CB2 agonists act via the CB2 receptor to inhibit a common transcription factor, NF-?B, regulating multiple cytokines/chemokines. We propose to use behavioral, biochemical, immune and molecular strategies to test whether MAGL inhibition and/or CB2 agonist, in the presence of morphine (standard clinical care) will be a beneficial therapy for breast-induced bone cancer pain. This hypothesis will be tested by the following Aims using our syngeneic (non-immune-compromised) murine model of CIBP: Aim 1. Determine whether the inhibition of MAGLipase attenuates breast cancer-induced bone pain and/or alter bone resorption and remodeling. Aim 2. Explore whether MAGLipase inhibition and CB2 receptor activation attenuates breast cancer-induced bone pain by inhibiting pronociceptive cytokines/chemokines via a common transcription factor. Aim 3. Determine whether a MAGL inhibitor and the activation of the CB2 and Mu opioid receptors result in the synergistic inhibition of breast cancer-induced bone pain while reducing bone loss. These studies will lead to urgently needed new treatments and may likely apply to other metastatic cancers, including lung and prostate.

Project Summary Biochemical Core: Approximately 100 million American adults suffer from chronic pain with a societal cost of approximately $600 billion annually (Institute of Medicine 2011. Opioids effectively alleviate pain for many of these patients, but are limited by the development of adverse events (e.g. nausea, constipation, dependence) and decreased efficacy at tolerable doses over time. Despite a myriad of analgesic compounds on the market, nearly two-thirds of patients report inadequate pain relief while the risks associated with opioid addiction have increased. In the US, prescribed opioids have become the leading abused drugs and top reasons of injury death in the United States. While many studies in the last 15 years concerning opioid abuse have examined the idea that both injury and sustained opioid therapy can induce neuroplastic adaptations, no drug-development strategies have targeted such changes. These changes include endogenous increases in neurokinins, cholecystokinins and enzymes that rapidly degrade endogenous cannabinoids (i.e., FAAH, MAGL) after injury and in some cases after sustained opioid use. Antagonists to the neurokinin receptor-1 and to the CCK receptors-1&2 have been shown to be opioid sparing while decreasing many opioid induced side effects including rewarding behaviors in animals. In addition, many separate studies have identified analgesic efficacy of CB1 and CB2 compounds in animal models of chronic pain, yet no studies have investigated making a bifunctional compound of a CB2 agonist, CB1 neutral antagonist/partial agonist or CB1/CB2 peripherally restricted agonists for chronic pain with reduced unwanted effects. Here we propose to test synthesized compounds with dual activity that includes opioid receptor agonism and either NK-1 (project A), CCK1/2 (project B) antagonism, or CB2-agonist/CB1-antagonist and peripherally restricted mixed CB1/2 agonists (project C) in order to increase analgesic efficacy while inhibiting unwanted side effects with improved drug stability & delivery. The Biochemical Core will provide the necessary screening of novel compounds synthesized by the Chemistry Core based on the knowledge and findings from each of the projects. Due to our years of experience in in vitro and in vivo studies, we will perform 6 aims to efficiently screen all compounds in a highly resourceful manner that will provide feedback to chemistry at all levels in order to develop the best analgesics for chronic pain. These include Aim 1, receptor binding for opioid, NK1, CCK, CB receptors, Aim 2, in vitro functional assays to determine agonist/antagonist activity as well as efficacy, Aim 3, in vivo assays for analgesic/anti-inflammatory activity, Aim 4, in vivo assay in a model of neuropathic pain, Aim 5, in vivo assays for unwanted side effects and Aim 6, In vivo pharmacokinetics. Once compounds have been shown to have efficacy in a model of neuropathic pain (aim 4) the compounds will be tested concurrently in aims 5 and 6. In vitro screening for project C (aims 1 and 2) will be performed in Dr. Makriyannis's laboratory due to having many years of experience in screening of cannabinoid compounds. In vivo screening will be in Biochemical core and labs of Drs. Porreca and Vanderah. These compounds designed to have multiple targets in order to increase analgesic efficacy by addressing endogenous changes due to injury while minimizing the unwanted side effects of opioids alone including opioid addiction. These compounds will entail design for improved plasma stability, CNS penetration, and acceptable pharmacokinetics for movement into clinical trials. The Biochemical Core contains 6 aims in order to properly screen 30-80 novel compounds/yr allowing for a highly efficient structure-activity-relationship (SAR) feedback for improved compound design as noted in our flow chart.  

Opioid use for chronic pain is limited by antinociceptive tolerance, opioid-induced hyperalgesia (OIH), physical dependence and addiction.1-3 The triggering mechanisms remain elusive. Our published work4,5 and preliminary data suggest for the first time that dysregulation of sphingolipid metabolism in the central nervous system (CNS) leading to exaggerated production of sphingosine 1-phosphate (S1P) and activation of an astrocyte-based S1P receptor subtype 1 (S1PR1) signaling pathway is central to these processes. Oral administration of CNS penetrant S1PR1 competitive and functional antagonists, including FTY720 (Gilenya®),6 blocked morphine and oxycodone-induced antinociceptive tolerance and OIH in rodents of both genders, as well as morphine-induced dependence and reward. FTY720 is already FDA-approved6 and therefore, rapid clinical translation of the expected finding is very feasible. We also discovered that sustained opioid-unwanted actions do not develop in conditional S1PR1-knockout mice lacking S1PR1 in spinal astrocytes and that the beneficial effects of S1PR1-targeted agents are attenuated by at least 90% in conditional S1PR1-knockdown mice of both genders, which lack one S1pr1 allele in spinal astrocytes when compared to their littermate controls. These results unravel the importance of astrocyte-based S1PR1 signaling and suggest that astrocytes are a cellular target for anti-S1PR1 activity. Increased levels of S1P in CNS were associated with increased 1) astrocyte reactivity, 2) expression of the Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome (critical in IL1? formation and signaling)7 and 3) formation of inflammatory/ neuroexcitatory cytokines. Blocking S1PR1 inhibited these processes. In contrast, IL10 (an important anti- inflammatory and neuroprotective cytokine) increased significantly. Intrathecal delivery of a neutralizing anti- IL10 antibody blocked the effects of S1PR1 antagonists suggesting that their beneficial effects are driven by an endogenous IL10 pathway. A multidisciplinary plan builds on our strong preliminary data to test our hypothesis: An astrocyte-based SphK1/S1P/S1PR1 signaling pathway driven by NLRP3-induced neuroinflammation in the CNS underlies the development of morphine-induced antinociceptive tolerance/OIH and reward. Targeting S1PR1 provides a novel approach for therapeutic intervention. Three aims will test our hypothesis: 1) Establish S1PR1 as a molecular target for sustained opioid intervention, 2) Examine opioid-induced alterations of sphingolipid metabolism and SphK1/S1P/S1PR1 signaling and 3) Determine molecular and biochemical pathways engaged downstream of S1PR1 activation. Impact: Our results will unravel a previously unrecognized role for an astrocyte based SphK1/S1P/S1PR1- signaling pathway in sustained opioid use and will provide the foundation for clinical evaluation of S1PR1- targeted therapeutics as adjunct to opioids.

PROJECT SUMMARY/ABSTRACT Physician scientists are widely respected as a crucial ?bridge? between bench and bedside, conducting rigorous and relevant research to provide their field with novel, evidence-based interventions for improved treatment and outcomes of patients. This intersectional career comes with distinctive challenges and responsibilities. While ripe for collaborations and interdisciplinary projects, the workforce lags in terms of representation of women and minorities compared to the traditional physician training. The American Physician Scientist Association (APSA) is a student led organization, by trainees, for trainees, and strives to be the student physician-scientists' leading voice for improving educational opportunities, advancing patient-oriented research, and advocating for the future of translational medicine. The University of Arizona College of Medicine is honored to host the 2020 APSA West Regional Meeting to promote novel interdisciplinary collaborations, support for underrepresented students in the field of academic medicine, and meaningful discussions on our responsibilities as chimeras in the world of science and medicine. The overarching goal of the 2020 APSA West Regional Meeting is to foster meaningful relationships amongst all stages of future and current physician scientists. These relationships are an essential piece in the successful navigation of the unique path toward a career as a clinical investigator and will contribute to the long-term goal of advancing patient-centered research.

Project Summary/Abstract. (30 lines) Our mission within the UA COM-T, MD-PhD Program is to develop a diverse pool of highly trained physician- scientists who have the aptitude to utilize clinical experience in developing biomedical hypotheses that integrate the research skills learned in our program. We intend to have all trainees independent, productive and rewarding physician-scientist careers. This program has established 6 objectives that include; 1) dual- degree completion rates at >97% with an appropriate time-to-degree (7.3 yrs on avg.), 2) the integration of research and clinical activities, 3) nurture a broad understanding of biomedical disciplines, 4) foster and encourage the development of good scientific premise, rigorous-research design, strong experimental methods with reproducibility/validation, as well as skills to analyze and interpret results/outcomes amid ethics and integrity, 5) build proficiency in initiating, conducting, interpreting, and presenting rigorous and reproducible biomedical research with increasing self-direction, while strengthen skills to teach and communicate, and 6) fortify diversity while advancing the knowledge, professional skills, and experiences required to identify and transition into productive careers in the biomedical research workforce that utilize the dual-degree training. UACOM-T MD-PhD Program offers a wide range of biomedical disciplines for trainees with 13 graduate programs available and over 60 faculty trained and excited to be mentors. Our rationale for an NIH-MSTP is the desperate need for the increase in Physician-Scientists in the state of AZ; a population that is rapidly growing and aging with multiple medical and research needs. AZ is the fourth most populous state for Hispanics and has the third largest Native American population in the US. UArizona is designated as both a Hispanic and American Indian/Alaska Native Serving Institution. UArizona has a strong understanding of the concerns of diverse individuals with behavioral health needs, excels in cultural competency, and has long recognized its unique mission and obligation to serve all of the diverse peoples and communities. UArizona has more than doubled its enrollment of URMs in the last 10 years, comprising 20% of all graduate students, placing UArizona at the top of all Research I, AAU-member institutions. Hence, the UA COM-T is a perfect institution to serve and uphold the goals and intentions of the MSTP by increasing the number of URMs as physician scientist. The current MD-PhD program has been funded entirely by support from the institution resulting in a small but overall very successful cohort of physician scientists with past trainees in academic positions at Stanford, Harvard, Yale, Vanderbilt, Baylor, OHSU, Scrips, etc. Our program has established a comprehensive 7-year training plan that reduces unnecessary redundancies, utilizes evidence based medicine training, integrates clinical and research over all 7 years while creating and encouraging an inclusive climate.

We propose to establish a Center of Excellence for Addiction Studies (CEAS) that will offer core services allowing users to develop projects that will lead to new research in addiction. Addiction and relapse are characterized by dysregulation of brain circuitry that involves diminished activity of brain reward circuits, increased responsiveness of stress circuits and impaired functioning of executive cortical circuits. Neural changes are observed in the basal ganglia, extended amygdala and prefrontal cortical regions and encompass a wide range of endogenous neurotransmitters including dopamine, opioid peptides, endocannabinoids, corticotropin releasing factor (CRF), dynorphin, glutamate and others. While chronic pain and addiction are different disorders, there is a remarkable overlap between the influence of drugs of abuse and chronic pain on these circuits. Our faculty has broad expertise in evaluation of mechanisms that underlie the maladaptations promoted by pain in these circuits. The CEAS will be composed of four Cores and a Pilot Research Project. The Administrative Core will provide the structural elements that will allow efficient functioning of the CEAS. The Genetic Targeting of Neural Circuits Core will allow users to employ cutting edge genetic techniques including CRISPR/Cas9 gene editing, chemogenetics and optogenetics to produce cell and circuit-specific manipulations to evaluate potential mechanisms relevant to addiction. The Neuroanalytical Core will provide users with advanced methods of measuring neurotransmitters with temporal resolution spanning milli-seconds to days and with spatial specificity through advanced detection methods. The Behavioral Core will allow users to explore questions relevant to addiction using behavioral assays that evaluate addictive processes including the influence of addictive drugs on cognitive function. Investigators in the CEAS have worked together for many years and have shared and individual research funding. Additionally, the CEAS will offer opportunities for other investigators at University of Arizona as well as Arizona State University, Northern Arizona University, The University of New Mexico and Texas Tech University Health Sciences Center at Lubbock and El Paso establishing a Southwestern region engaged in addiction sciences. The CEAS will promote increased diversity in addiction research by recruiting investigators and students from under-represented populations in neuroscience and addiction. The impact of the CEAS will be to leverage established funding to develop new research on addiction research. In addition, the impact of funds from the CEAS will be amplified by commitments of matching funds from the University of Arizona and from a recently established Comprehensive Center of Pain and Addiction. The CEAS will provide key services to its users that correspond with the goals of the NIDA to enhance addiction research with a goal of development of therapies that can stem the opioid epidemic as well as impacting other substance abuse disorders. The close collaboration between the Cores ensures high expertise in all areas of the addiction research and will permit outcome measures emphasizing scientific rigor and reproducibility.