Non-Human Primate Model for Systems Biology Studies of Stress Response

描述(由申请人提供)：对心理社会应激源的行为和生理反应可以预测暴露在压力下的长期健康后果。这些后果包括心脏代谢性疾病、成瘾和精神障碍的风险显著增加。然而，人们对压力易感性个体间差异背后的遗传差异，以及为这种差异提供假定机制的基因表达模式知之甚少。我们建议使用加勒比斑尾猴(ChlorOcean Bus AtheiopsSabaeus)建立一个非人类灵长类动物(NHP)的翻译模型，用于压力响应性研究，这将有助于研究急性心理社会应激源对生理、行为和认知的多系统影响。这些研究在人类身上是不可行的，也不能在啮齿动物身上进行可靠的建模，因为啮齿动物在这些系统上与人类有太大的不同。我们将利用常规应用于圣基茨岛上野生被困芦荟的短期隔离程序来调查假设与应激反应有关的多系统措施。具体地说，我们将纵向监测受压力调节的基因和基因网络的表达，这些基因和基因网络预测个体对压力的行为和生理敏感性的差异。这项概念验证研究将通过以下几个方面验证所提出的模型：1)证明应激源对新陈代谢、炎症和行为反应的影响；2)表征与应激相关的特征的个体间差异；3)显示应激诱导的高阶表型变化与基因表达模式之间的机制联系。这一模型的发展将在短期内提供对应激相关疾病的分子基础的洞察，并在长期内为大规模的遗传和基因组研究铺平道路，以确定个体对应激反应的差异的基础。

DESCRIPTION (provided by applicant): Behavioral and physiological responses to psychosocial stressors can predict the long-term health consequences of exposure to stress. These consequences include dramatically elevated risks for cardiometabolic diseases, addictions, and mental disorders. Little is known, however, about either the genetic variation underlying inter-individual variation in susceptibility to stress, or about the gene expression patterns that provide the presumed mechanism for such variation. We propose to create, using the Caribbean vervet monkey (Chlorocebus aethiops sabaeus), a translational non-human primate (NHP) model for stress responsivity studies, which will facilitate investigations of the multi-system effects of an acute psychosocial stressor on physiology, behavior and cognition. These investigations are not feasible in humans, and cannot be reliably modeled in rodents, which differ from humans too substantially in these systems. We will leverage the short-term quarantine procedures applied routinely to wild-trapped vervets on the island of St. Kitts to investigate multi-system measures hypothesized to be associated with stress-responsivity. Specifically, we will longitudinally monitor expression of genes and gene networks that are stress-regulated and that predict individual differences in behavioral and physiological sensitivit to stress. This proof of concept study will validate the proposed model by: 1) demonstrating the impact of the stressor on metabolic, inflammatory and behavioral responses; 2) characterizing inter-individual variations in stress-related traits; 3) showing mechanistic links between stress-induced changes in higher-order phenotypes and gene expression patterns. Development of this model will, in the short-term provide insights into the molecular underpinnings of stress- related diseases, and, in the long-term, pave the way for large scale genetic and genomic investigations to identify the basis for individual differences in response to stress.