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

在非人类灵长类动物模型中建立大脑结构变异的 miRNA 生物标志物特征

• 批准号: 9375787
• 负责人: Melanie Carless
• 金额: $ 29.43万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9375787
• 关键词: Accounting; Address; Affect; Age; Aging; Amygdaloid structure; Animal Model; Anterior; Automobile Driving; Behavior; Behavioral; Biological; Biological Markers; Biology; Blood; Blood Cells; Brain; Brain region; Cerebrospinal Fluid; Clinical; Clinical Trials; Complex; Data; Development; Disease; Dorsal; Epilepsy; Female; Goals; Hair; Health; Hippocampus (Brain); Human; Human Biology; Human Pathology; Impaired cognition; Insula of Reil; Link; Magnetic Resonance Imaging; Measures; Medial; Mental Depression; Mental disorders; MicroRNAs; Mission; Modality; Modeling; Molecular; Morbidity - disease rate; Neuraxis; Neurologic; One-Step dentin bonding system; Outcomes Research; Papio; Pathology; Peripheral; Pharmacologic Substance; Pharmacology; Phenotype; Physiological; Physiology; Plasma; Population; Pre-Clinical Model; Primates; Public Health; RNA; Research; Rodent Model; Source; Structure; Technology; Thalamic structure; Therapeutic; Therapeutic Agents; Thick; Translations; United States National Institutes of Health; Variant; Work; aged; animal model development; base; cingulate cortex; disability; disability-adjusted life years; disease phenotype; entorhinal cortex; exosome; genetic manipulation; improved; male; microRNA biomarkers; model development; mortality; nervous system disorder; neuroimaging; neuropsychiatric disorder; next generation sequencing; nonhuman primate; novel; novel therapeutics; pre-clinical; preclinical development; preclinical study; response; socioeconomics; success; symptom treatment; targeted treatment; therapy development; therapy outcome; translational study; treatment response

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.

项目摘要 神经精神疾病构成了美国残疾调整的生命年最大的来源， 占所有原因的20％的残疾。尽管有重大的健康威胁和严重的社会经济 影响，研究很少来指导新的治疗发展，这导致了大量的研究 减少了发现药品机构新药的努力。临床试验的流失率为 与中枢神经系统相关的疗法的成功率极高，成功率仅为8％。这 啮齿动物模型之间的行为，生理和生物学的巨大差异，传统上是模型 对于临床前研究和人类的选择，几乎可以肯定会对这些高流失率产生重大贡献。 这项研究的最终目的是为狒狒作为临床前模型提供证据 神经精神疾病。为此，将解决以下具体目标： 1。确定32（16名男性和16位女性）健康和老化的狒狒的大脑结构变化 2。确定狒狒大脑中结构变化的miRNA生物标志物特征。 使用磁共振成像（MRI）和下一代测序技术，miRNA生物标志物将 可以鉴定出与七个大脑区域的体积或皮质厚度相关的 人类研究中多种神经精神疾病 - 海马，杏仁核，丘脑，背部前部 扣带皮层，岛岛，内侧眶额皮质和内嗅皮层。先前的证据已经存在 支持狒狒模型进行神经影像学研究，包括大脑明显大于其他灵长类动物， 其中包括在人类中发现的所有主要皮质结构，以及更高程度的回旋化。为了 捕获最相关的生物标志物特征miRNA表达将在外周血细胞中评估， 脑脊液（CSF），在源自血浆和CSF的外泌体中与神经解剖学相关 变化。为了确定这种生物标志物对神经精神疾病的潜在重要性，这是一个独立的 狒狒组将用于确定外周miRNA生物标志物与脑miRNA之间的相关性 通过神经影像评估的那些大脑区域的表达。 通过将外围miRNA生物标志物与脑区域的神经解剖学变异和miRNA表达联系起来 对于神经精神疾病来说重要的是，对这些疾病的生物学的更全面了解可能是 成就了。如果人类与狒狒之间存在与大脑结构有关的类似的生物学关系， 这为狒狒作为神经精神疾病的临床前模型提供了支持，这可能 加快临床试验成功的改善。