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

项目总结 在美国，神经精神疾病是残疾调整生命年的最大单一来源。 占所有原因致残的20%。尽管存在严重的健康威胁和严重的社会经济问题 影响，缺乏指导新疗法开发的研究，这导致了大量的 减少制药机构发现新药的努力。临床试验的流失率是 非常高，与中枢神经系统相关的治疗成功率仅为8%左右。这个 啮齿动物模型之间在行为、生理和生物学方面的巨大差异，这些模型传统上是 临床前研究的选择，以及人类，几乎肯定是导致这些高磨损率的重要原因。 这项研究的最终目标是提供证据，证明狒狒作为临床前疾病模型的实用性。 神经精神疾病。为实现这一目标，将实现以下具体目标： 1.确定32只(雄16只，女16只)健康和老年狒狒的脑结构变异 2.确定狒狒大脑结构变异的miRNA生物标记物特征。 利用磁共振成像(MRI)和下一代测序技术，miRNA生物标记物将 在七个脑区中发现与体积或皮质厚度相关的基因 人类研究中的多种神经精神疾病--海马体、杏仁核、丘脑、背侧前部 扣带回皮质、脑岛、内侧眶前叶皮质和内嗅觉皮质。先前的证据已经存在于 支持用于神经成像研究的狒狒模型，包括比其他灵长类动物大得多的大脑， 这包括在人类中发现的所有初级皮质结构，以及更高程度的回旋化。为了 捕获最相关的生物标记物签名miRNA表达将在外周血细胞中进行评估， 脑脊液，以及从血浆和脑脊液衍生的外体中，与神经解剖学相关 变种。为了确定这些生物标记物对神经精神疾病的潜在重要性，一个独立的 将使用一组狒狒来确定外周miRNA生物标记物和大脑miRNA之间的相关性 通过神经成像评估这些脑区的表达。 通过将外周miRNA生物标记物与神经解剖变异和脑区miRNA表达联系起来 对于神经精神疾病来说，对这些疾病的生物学有更全面的了解可能是 已实现。如果在与脑结构有关的人类和狒狒之间存在相似的生物关系， 这支持了将狒狒作为神经精神疾病的临床前模型的实用性，这可能 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.