(provided by candidate): This proposal outlines a five year program to train a child psychiatrist to study the molecular pathophysiology of autism. Autism spectrum disorders affect as many as 1 in 160 children. Little is known concerning the genetic determinants of autism pathophysiology, limiting treatment and prevention strategies. The candidate has completed clinical training in child psychiatry and concurrent research training in human molecular genetics. He proposes to learn a new set of scientific skills to use transgenic mice to model alterations of the serotonin system in autism. The training program centers on techniques to analyze the brain and platelet serotonin system, as well as methodology to study resulting changes in mouse brain morphology and behavior. Recent genetic and biochemical studies implicate genetic and physical interactions of the integrin 33 and serotonin transporter genes in the determination of platelet serotonin levels as well as autism traits. The candidate proposes to use transgenic mice to understand the impact of variation in these two genes.
The Specific Aims i nclude brain and behavioral analyses of: 1) Mice with decreased or absent expression of integrin (33; 2) Mice expressing an overactive serotonin transporter 425Leu variant; and 3) Mice heterozygous for both integrin p3 and serotonin transporter variants to model interaction effects of common human variation. The candidate's mentor, Dr. Randy Blakely, is an internationally respected researcher in the field of neurotransmitter transporters and has an active, well-funded laboratory in the candidate's field of interest. He has trained numerous graduate students and postdoctoral fellows in the study of monoamine transporter proteins, including the production and characterization of transgenic mice. To add further expertise, Dr. Jacqueline Crawley, a specialist in murine models of autism, will advise on mouse behavioral studies, and Dr. Elaine Sanders-Bush will advise on serotonin receptor studies. The Department of Psychiatry and the Center for Molecular Neuroscience at Vanderbilt present an ideal setting for the candidate's development. Vanderbilt's collective expertise in molecular research on the serotonin system and strong commitment to autism research provide an unparalleled opportunity to advance the candidate's career development toward the goal of developing an independent research program relevant to child psychiatry. ? ?
|Nackenoff, Alex G; Moussa-Tooks, Alexandra B; McMeekin, Austin M et al. (2016) Essential Contributions of Serotonin Transporter Inhibition to the Acute and Chronic Actions of Fluoxetine and Citalopram in the SERT Met172 Mouse. Neuropsychopharmacology 41:1733-41|
|Mazalouskas, Matthew; Jessen, Tammy; Varney, Seth et al. (2015) Integrin ?3 Haploinsufficiency Modulates Serotonin Transport and Antidepressant-Sensitive Behavior in Mice. Neuropsychopharmacology 40:2015-24|
|Saunders, Christine; Siuta, Michael; Robertson, Sabrina D et al. (2014) Neuronal ablation of p-Akt at Ser473 leads to altered 5-HT1A/2A receptor function. Neurochem Int 73:113-121|
|Shah, Charisma R; Forsberg, Carl Gunnar; Kang, Jing-Qiong et al. (2013) Letting a typical mouse judge whether mouse social interactions are atypical. Autism Res 6:212-20|
|Stewart, S E; Mayerfeld, C; Arnold, P D et al. (2013) Meta-analysis of association between obsessive-compulsive disorder and the 3' region of neuronal glutamate transporter gene SLC1A1. Am J Med Genet B Neuropsychiatr Genet 162B:367-79|
|Veenstra-VanderWeele, Jeremy (2012) In this issue/abstract thinking: evolving picture of susceptibility factors in autism spectrum disorders. J Am Acad Child Adolesc Psychiatry 51:453-4|
|Veenstra-VanderWeele, Jeremy; Xu, Tim; Ruggiero, Alicia M et al. (2012) Functional studies and rare variant screening of SLC1A1/EAAC1 in males with obsessive-compulsive disorder. Psychiatr Genet 22:256-60|
|Veenstra-VanderWeele, Jeremy; Blakely, Randy D (2012) Networking in autism: leveraging genetic, biomarker and model system findings in the search for new treatments. Neuropsychopharmacology 37:196-212|
|Veenstra-VanderWeele, Jeremy; Muller, Christopher L; Iwamoto, Hideki et al. (2012) Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior. Proc Natl Acad Sci U S A 109:5469-74|
|Hammock, Elizabeth; Veenstra-VanderWeele, Jeremy; Yan, Zhongyu et al. (2012) Examining autism spectrum disorders by biomarkers: example from the oxytocin and serotonin systems. J Am Acad Child Adolesc Psychiatry 51:712-721.e1|
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