My research focuses on the genetic variance that underlies substance abuse and neuropsychiatric disorders, and also the basic neurobiological mechanisms of addictive drugs. Under this award, I will model components of human serotonergic neurogenetic variance underlying drug addiction, alcoholism and neuropsychiatric disorders in rhesus monkeys. Though rhesus monkeys often harbor different alleles than occur in humans, genetic variants in this species have common functionality compared with those in orthologous human genes known to contribute to the variance of neuropsychiatric and addictive disease. I will systematically uncover functionally comparable polymorphisms in rhesus monkey serotonin transporter (SERT), tryptophan hydroxylase 2 (TPH2) and monoamine oxidase A (MAOA) genes, and assess genotype/phenotype relationships relevant to drug addiction, alcoholism and neuropsychiatric disorders. By selecting rhesus monkeys that naturally harbor an array of comparable functional alleles in these serotonergic genes, I will study genetic interactions influencing disorder-related phenotypes and develop a highly translational preclinical platform for the development of pharmacogenomic-informed human personalized medicine. The theme of developing novel therapeutics for addiction and psychiatric disorders extends to a complimentary research focus on the regulation of brain monoaminergic systems and the role of Trace Amine Associated Receptor 1 (TAAR1). TAAR1 is a primary target of monoamines and amphetamine like drugs. Under this award, I will study the role of TAAR1 in brain, the immune system, and the periphery. My recent work on TAAR1 strongly suggests that the receptor is a target for the development of novel therapeutics for neuropsychiatric and addiction disorders and particularly, for methamphetamine addiction. I will pursue these leads through a molecular screening approach and through assessment of novel compounds in vitro and in vivo. Both research programs join with my proposed study of the TAAR1 gene, which has polymorphisms that may underlie differences in receptor function or expression in both humans and rhesus monkeys. Under this award, I will be freed from administrative, committee, core and consortium responsibilities, so that I can devote more time (>75%) to conducting research and to activities that are directly related to the further development of my independent research career and mentoring of trainees. I will also participate in a variety of training experiences in the responsible conduct of research, and create a seminar presentation on research ethics that I will deliver to our community of researchers and students.
Rhesus monkeys have close genetic and physiological similarities with humans that underlie parallel behavioral, developmental, physiological, and metabolic activities. The proposed research identifies genetic variations in rhesus monkey genes that naturally mimick the function of those underlying neuropsychiatric and addictive disorder variance in humans, and models genotype/phenotype relationships relevant to basic neurobiological mechanisms and the pharmacogenomics of drugs of abuse.
|Chen, Guo-Lin; Ma, Qi; Goswami, Dharmendra et al. (2017) Modulation of nuclear REST by alternative splicing: a potential therapeutic target for Huntington's disease. J Cell Mol Med 21:2974-2984|
|Lynch, Laurie J; Sullivan, Katherine A; Vallender, Eric J et al. (2013) Trace amine associated receptor 1 modulates behavioral effects of ethanol. Subst Abuse 7:117-26|
|Chen, Guo-Lin; Miller, Gregory M (2013) Extensive alternative splicing of the repressor element silencing transcription factor linked to cancer. PLoS One 8:e62217|
|Chen, Guo-Lin; Miller, Gregory M (2013) Tryptophan hydroxylase-2: an emerging therapeutic target for stress disorders. Biochem Pharmacol 85:1227-33|
|Vallender, Eric J; Miller, Gregory M (2013) Nonhuman primate models in the genomic era: a paradigm shift. ILAR J 54:154-65|
|Chen, Guo-Lin; Miller, Gregory M (2012) Advances in tryptophan hydroxylase-2 gene expression regulation: new insights into serotonin-stress interaction and clinical implications. Am J Med Genet B Neuropsychiatr Genet 159B:152-71|
|Panas, Michael W; Xie, Zhihua; Panas, Helen N et al. (2012) Trace amine associated receptor 1 signaling in activated lymphocytes. J Neuroimmune Pharmacol 7:866-76|
|Miller, Gregory M (2012) Avenues for the development of therapeutics that target trace amine associated receptor 1 (TAAR1). J Med Chem 55:1809-14|
|Achat-Mendes, Cindy; Lynch, Laurie J; Sullivan, Katherine A et al. (2012) Augmentation of methamphetamine-induced behaviors in transgenic mice lacking the trace amine-associated receptor 1. Pharmacol Biochem Behav 101:201-7|
|Lewin, Anita H; Miller, Gregory M; Gilmour, Brian (2011) Trace amine-associated receptor 1 is a stereoselective binding site for compounds in the amphetamine class. Bioorg Med Chem 19:7044-8|
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