Establishing a miRNA biomarker signature for brain structural variation in a non-human primate model

项目摘要 神经精神疾病是美国残疾调整生命年的最大来源， 占所有原因造成的残疾的20%。尽管存在严重的健康威胁和严重的社会经济问题， 影响，缺乏研究来指导新的治疗开发，这导致了大量的 减少制药机构发现新药的努力。临床试验的损耗率为 非常高，与中枢神经系统相关的治疗成功率仅为8%左右。的 啮齿类动物模型之间在行为、生理和生物学方面存在巨大差异， 临床前研究的首选药物，以及人类，几乎肯定会对这些高损耗率做出重大贡献。 这项研究的最终目标是为狒狒作为临床前模型的实用性提供证据， 神经精神疾病为实现这一目标，将致力于实现以下具体目标： 1.识别32只（16只雄性和16只雌性）健康和老年狒狒脑结构的变化 2.确定狒狒大脑结构变异的miRNA生物标志物特征。 利用磁共振成像（MRI）和下一代测序技术，miRNA生物标志物将 与七个大脑区域的体积或皮质厚度相关， 人类研究中的多种神经精神疾病-海马体、杏仁核、丘脑、背前 扣带皮质、岛叶、内侧眶额皮质和内嗅皮质。先前的证据已经存在于 支持狒狒模型用于神经成像研究，包括比其他灵长类动物大得多的大脑， 包括人类所有的初级皮质结构和更高程度的脑回化。为了 捕获最相关的生物标志物标签miRNA表达将在外周血细胞中评估， 在脑脊液（CSF）中，以及在来源于血浆和CSF的外泌体中，用于与神经解剖学相关。 变化量为了确定这些生物标志物对神经精神疾病的潜在重要性，一项独立的 一组狒狒将用于确定外周miRNA生物标志物和脑miRNA之间的相关性 通过神经成像评估这些大脑区域的表达。 通过将外周miRNA生物标志物与脑区神经解剖学变异和miRNA表达联系起来， 重要的是神经精神疾病，更全面地了解这些疾病的生物学， 办妥了一批如果人类和狒狒在大脑结构上存在类似的生物学关系， 这支持狒狒作为神经精神疾病的临床前模型的实用性， 加快提高临床试验成功率。

PROJECT SUMMARY Neuropsychiatric diseases constitute the single largest source of disability-adjusted life years in the US, accounting for 20% of disability from all causes. Despite the significant health threat and severe socioeconomic impact, there is a paucity of studies to guide novel treatment development and this has led to substantial reductions in the effort to discover new drugs by pharmaceutical agencies. The attrition rate of clinical trials is extremely high, with success rates of only about 8% for therapies related to the central nervous system. The vast differences in behavior, physiology, and biology between rodent models, which are traditionally the model of choice for preclinical studies, and humans, almost certainly contribute significantly to these high attrition rates. The ultimate goal of this research is to provide evidence for the utility of baboons as a preclinical model for neuropsychiatric diseases. To achieve this, the following Specific Aims will be addressed: 1. Identify variation in brain structure of 32 (16 male and 16 female) healthy and aged baboons 2. Determine a miRNA biomarker signature of structural variation in the brains of baboons. Using magnetic resonance imaging (MRI) and next-generation sequencing technologies, miRNA biomarkers will be identified that are associated with either volume or cortical thickness in seven brain regions implicated in multiple neuropsychiatric diseases in human studies - hippocampus, amygdala, thalamus, dorsal anterior cingulate cortex, insula, medial orbitofrontal cortex, and entorhinal cortex. Prior evidence already exists in support of a baboon model for neuroimaging studies, including significantly larger brains than other primates, which include all primary cortical structures found in humans, and a higher degree of gyrification. In order to capture the most relevant biomarker signature miRNA expression will be assessed in peripheral blood cells, cerebrospinal fluid (CSF), and in exosomes derived from plasma and CSF for association with neuroanatomical variation. To establish the potential importance of such biomarkers to neuropsychiatric disease, an independent group of baboons will be used to determine correlations between peripheral miRNA biomarkers and brain miRNA expression in those brain regions assessed via neuroimaging. By linking peripheral miRNA biomarkers to neuroanatomical variation and miRNA expression in brain regions important for neuropsychiatric disease, a more complete understanding of the biology of these diseases can be achieved. If similar biological relationships exist between humans and baboons with relation to brain structure, this lends support to the utility of baboons as a preclinical model for neuropsychiatric diseases, which may expedite the improvement of clinical trial success.