Modeling the Neurogenetics of Serotonin Regulation

描述(申请人提供)：5-羟色胺能在精神健康中起重要作用，功能障碍与许多突出的精神健康障碍有关，包括抑郁症、精神分裂症和成瘾性人格障碍。本应用旨在探索恒河猴5-羟色胺转运体(SERT)和单胺氧化酶A(MAOA)基因的神经遗传学多样性。在人类中，这些基因的变异与个人对一系列精神健康疾病的相对脆弱性或保护性有关。本研究的目的是在体外研究恒河猴这些基因的功能多态和单倍型，并找出在效果上自然模仿神经精神障碍的特定人类多态的变异。具体目的是评估恒河猴SERT和MAOA基因的多态和单倍型的发生率，探索某些恒河猴SERT和MAOA变体在体外是否具有与人类同源单倍型平行的功能，并开发利用自然发生的恒河猴遗传变异来建立人类神经遗传变异的非人类灵长类动物模型。该研究计划的宏伟目标是识别拥有多个等位基因变异的恒河猴群体，这些变异在功能上与人类等位基因变异平行，并与灵长类动物特有的表型有关，与精神健康疾病有关。我们在NEPRC的1100多只遗传多样化恒河猴群体中识别和表征功能性SERT和MAOA多态，将通过加快我们利用这一独特而有价值的资源阐明影响不同表型、生理、行为和性状差异的遗传交互作用的能力，增强我们在该动物种群中不断增长的基因/表型评估。在这方面，这项申请探索了使用选定的NEPRC恒河猴队列作为具有非凡翻译有效性的人类精神健康研究的“自然主义”动物模型的可行性，以及它们作为开发基于药物基因组学的人类治疗学的临床前平台的适宜性。相关性：了解神经精神疾病的遗传基础不仅有助于诊断和治疗选择，而且阐明个体之间的差异将提高疗效。开发这种变异的非人类灵长类动物模型不仅可以更好地检查这种疾病的机制和病理，还可以开发高度翻译的新型治疗方法。

DESCRIPTION (provided by applicant): Serotonergic tone plays an important role in mental health, with dysfunction implicated in many prominent mental health disorders including depression, schizophrenia, and addictive personality disorders. This application seeks to explore the neurogenetic diversity of serotonin transporter (SERT) and Monoamine Oxidase A (MAOA) genes in rhesus monkeys. In humans, variance in these genes is associated with an individual's relative vulnerability to or protection from a range of mental health disorders. The objective here is to characterize functional polymorphisms and haplotypes in these genes in rhesus monkeys in vitro, and to identify variations that naturally mimic in effect specific human polymorphisms implicated in neuropsychiatric dysfunction. Specific Aims are to assess the incidence of polymorphisms and haplotypes in rhesus monkey SERT and MAOA genes, to explore whether certain rhesus monkey SERT, and MAOA variants have parallel functionality to human orthologous haplotypes in vitro, and to develop the use of naturally-occurring rhesus monkey genetic variations to create non-human primate models of human neurogenetic variance underlying mental health disorders. The broad ambition of the research program is to identify cohorts of rhesus monkeys that harbor multiple allelic variants which functionally parallel human allelic variants and associate with primate-specific phenotypes relevant to mental health disorders. The identification and characterization of functional SERT and MAOA polymorphisms across our colony of more than 1100 genetically diversified rhesus monkeys at NEPRC will enhance our growing genotype/phenotype assessments in this animal population by accelerating our ability to use this unique and valuable resource to clarify genetic interactions influencing distinct phenotypic, physiological, behavioral and trait variances influencing mental health. In this regard, this application explores the feasibility of using selected cohorts of NEPRC rhesus monkeys as a "naturalistic" animal model with extraordinary translational validity for human mental health research, and their appropriateness as a preclinical platform for the development of human pharmacogenomics-based therapeutics. Relevance: Understanding the genetic basis of neuropsychiatric disease will not only facilitate diagnosis and treatment options, but the elucidation of differences between individuals will increase efficacy. Developing non-human primate models of this variation allows not only for a greater examination of the mechanisms and pathologies of the disease, but also allows for the development of highly translational novel treatments.