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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02DA025697-05
Application #
8472464
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Pollock, Jonathan D
Project Start
2009-07-15
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$123,055
Indirect Cost
$9,115
Name
Harvard University
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
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
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
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
Miller, Gregory M (2012) Avenues for the development of therapeutics that target trace amine associated receptor 1 (TAAR1). J Med Chem 55:1809-14
Westmoreland, Susan V; Annamalai, Lakshmanan; Lentz, Margaret R et al. (2011) Growth-associated protein-43 and ephrin B3 induction in the brain of adult SIV-infected rhesus macaques. J Neurovirol 17:455-68
Karmacharya, Rakesh; Lynn, Spencer K; Demarco, Sarah et al. (2011) Behavioral effects of clozapine: involvement of trace amine pathways in C. elegans and M. musculus. Brain Res 1393:91-9
Miller, Gregory M (2011) The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity. J Neurochem 116:164-76
Panas, Helen N; Lynch, Laurie J; Vallender, Eric J et al. (2010) Normal thermoregulatory responses to 3-iodothyronamine, trace amines and amphetamine-like psychostimulants in trace amine associated receptor 1 knockout mice. J Neurosci Res 88:1962-9
Chen, G-L; Novak, M A; Meyer, J S et al. (2010) TPH2 5'- and 3'-regulatory polymorphisms are differentially associated with HPA axis function and self-injurious behavior in rhesus monkeys. Genes Brain Behav 9:335-47

Showing the most recent 10 out of 14 publications