This is an application for the renewal of a senior scientist research and mentorship award to provide protected time for Ken Mackie so he can achieve the following goals for his research, mentoring, and career development. Specific research objectives during the next five years include: (1) Obtaining a comprehensive understanding of the mechanisms of CB1 cannabinoid receptor desensitization, (2) Discerning the roles of endogenous and exogenous cannabinoids during two key neurodevelopmental stages (A) during embryonic life and (B) during the adolescent maturation of the prefrontal cortex, (3) Exploring the therapeutic potential of CB2 cannabinoid receptor functional selectivity in making more effective analgesics and in attenuating cocaine reward, (4) Using simplified experimental systems (primarily cultured autaptic neurons) to address significant, outstanding issues in endocannabinoid-mediated synaptic plasticity. Dr. Mackie's mentoring will focus on mentoring four groups of scientists that encompass the full career spectrum: undergraduates at Indiana University, graduate and medical students at Indiana University, post-doctoral fellows, and junior faculty. His career development will emphasize the incorporation of more powerful imaging, informatic, proteomic, and behavioral tools into his research, as well as continuing to be heavily committed to service (editorial duties, meeting organization, and grant reviews) related to drug abuse research.
This application for a Senior Scientist Research and Mentorship Award seeks protected time for Ken Mackie, MD so that he may pursue research into the mechanisms of action of cannabis and endogenous cannabinoids and the consequence of their regular use. In the process of this he will also be mentoring students and faculty as they become drug abuse researchers.
|Zhong, Haixing; Tong, Li; Gu, Ning et al. (2017) Endocannabinoid signaling in hypothalamic circuits regulates arousal from general anesthesia in mice. J Clin Invest 127:2295-2309|
|Slivicki, Richard A; Xu, Zhili; Kulkarni, Pushkar M et al. (2017) Positive Allosteric Modulation of Cannabinoid Receptor Type 1 Suppresses Pathological Pain Without Producing Tolerance or Dependence. Biol Psychiatry :|
|Ruehle, Sabine; Wager-Miller, James; Straiker, Alex et al. (2017) Discovery and characterization of two novel CB1 receptor splice variants with modified N-termini in mouse. J Neurochem 142:521-533|
|Mitjavila, Jose; Yin, Danielle; Kulkarni, Pushkar M et al. (2017) Enantiomer-specific positive allosteric modulation of CB1 signaling in autaptic hippocampal neurons. Pharmacol Res :|
|Khurana, Leepakshi; Mackie, Ken; Piomelli, Daniele et al. (2017) Modulation of CB1 cannabinoid receptor by allosteric ligands: Pharmacology and therapeutic opportunities. Neuropharmacology 124:3-12|
|Xu, Changqing; Hermes, Douglas J; Nwanguma, Blessing et al. (2017) Endocannabinoids exert CB1 receptor-mediated neuroprotective effects in models of neuronal damage induced by HIV-1 Tat protein. Mol Cell Neurosci 83:92-102|
|Cinar, Resat; Gochuico, Bernadette R; Iyer, Malliga R et al. (2017) Cannabinoid CB1 receptor overactivity contributes to the pathogenesis of idiopathic pulmonary fibrosis. JCI Insight 2:|
|Dhopeshwarkar, Amey; Murataeva, Natalia; Makriyannis, Alex et al. (2017) Two Janus Cannabinoids That Are Both CB2 Agonists and CB1 Antagonists. J Pharmacol Exp Ther 360:300-311|
|Li, Ai-Ling; Carey, Lawrence M; Mackie, Ken et al. (2017) Cannabinoid CB2 Agonist GW405833 Suppresses Inflammatory and Neuropathic Pain through a CB1 Mechanism that is Independent of CB2 Receptors in Mice. J Pharmacol Exp Ther 362:296-305|
|Marcus, David J; Henderson-Redmond, Angela N; Gonek, Maciej et al. (2017) Mice expressing a ""hyper-sensitive"" form of the CB1 cannabinoid receptor (CB1) show modestly enhanced alcohol preference and consumption. PLoS One 12:e0174826|
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