Imaging alpha7-nAChRs in Traumatic Brain Injury

创伤性脑损伤中 α7-nAChR 的成像

• 批准号: 8761997
• 负责人: Andrew G Horti
• 金额: $ 20.25万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8761997
• 关键词: Acceleration; Acetylcholine; Acetylcholinesterase; Acute; Agreement; Alzheimer' s Disease; Animal Model; Animals; Anxiety; Astrocytes; Autonomic ganglion; Autoradiography; Awareness; Bilateral; Binding; Biochemical; Biological; Biological Markers; Brain region; Cerebrum; Choline; Complex; Control Animal; Data; Diagnostic; Diffuse; Disease; Drug Addiction; Event; Exhibits; Future; Goals; Hippocampus (Brain); Human; Image; Immunofluorescence Immunologic; In Vitro; Industry; Inflammation; Label; Laboratories; Link; Measures; Mediator of activation protein; Mental Depression; Microglia; Modeling; Multiple Sclerosis; Mus; Neuraxis; Neuroglia; Neurons; Nicotinic Receptors; Papio; Physiology; Positron-Emission Tomography; Primates; Property; Proteins; Public Health; Rattus; Reporting; Rodent; Schizophrenia; Sensory Ganglia; Severities; Side; Simulate; Site; Specificity; Staining method; Stains; TBI Patients; Traumatic Brain Injury; alpha-bungarotoxin receptor; base; brain tissue; controlled cortical impact; density; in vivo; innovation; macrophage; molecular imaging; nonhuman primate; novel; prognostic; public health relevance; radioligand; radiotracer; receptor; tool

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a major public health problem that raises the need to accurately measure its effects non-invasively. A biological target mechanistically linked to TBI and suitable for molecular imaging with diagnostic and prognostic implications could provide a quantitative non-invasive biomarker for TBI. Presently, such a biomarker does not exist. Multiple lines of evidence have demonstrated that TBI triggers a biochemical cascade that reduces the density of cerebral alpha7-nAChRs, one of the major subtypes of nicotinic acetylcholine receptors. Preliminary data from our laboratory has demonstrated that our novel positron-emission tomography (PET) radiotracer [18F]ASEM can accurately report the distribution of alpha7-nAChRs in control animals and that it exhibits strikin bilateral reduction of binding (32-73%) in rats with controlled cortical impact (CCI) TBI model. Currently, [18F]ASEM is the only alpha7-nAChR radioligand that has demonstrated excellent imaging properties with high specific binding in rodent and non-human primate PET studies. The main objective of this proposal is to validate the PET imaging properties of [18F]ASEM in two models of TBI in rats, focal - CCI and diffuse - impact acceleration (IA). 1) Cerebral alpha7-nAChR binding and distribution will be measured with [18F]ASEM - PET in CCI and IA models of TBI in rats. In agreement with previous in vitro alpha7-nAChR autoradiography data in animals with TBI reported by others and our preliminary PET results, our hypothesis is that the cerebral specific binding of [18F]ASEM in TBI will be significantly reduced. The reduction of the [18F]ASEM specific binding will correlate with the TBI severity and progression. 2) The PET results will be confirmed by immunofluorescent staining that will demonstrate significant alteration of the alpha7-nAChR protein in TBI rat brain tissue (in neurons and glia). The experimental focus of this proposal is to carry out proof-of-concept studies and obtain evidence of the suitability of [18F]ASEM for quantification of alpha7-nAChRs by PET in TBI models in rats. Our future goal is to evaluate alpha7-nAChRs as a potential biomarker of TBI in humans by studying the course of receptor changes in TBI and their sensitivity to the effects of various treatments.

描述（由申请人提供）：创伤性脑损伤（TBI）是一个主要的公共卫生问题，它提出了准确地衡量其效果的必要性。与TBI相关的生物学靶标，适用于具有诊断和预后意义的分子成像，可以为TBI提供定量的非侵入性生物标志物。目前，这种生物标志物不存在。多种证据表明，TBI触发了生化级联反应，该级联体降低了大脑α7-NACHR的密度，这是烟碱乙酰胆碱受体的主要亚型之一。 我们实验室的初步数据表明，我们的新型正电子发射层造影术（PET）radiotracer [18F] ASEM可以准确地报告对照动物中α7-NACHRS的分布，并且它在具有控制性皮质影响（CCI）模型的大鼠中表现出双边脱水的降低（32-73％）。目前，[18F] ASEM是唯一一种在啮齿动物和非人类灵长类动物宠物研究中表现出具有高特异性结合的出色成像特性的α7-NACHR放射线。该提案的主要目的是验证在大鼠，焦点-CCI和弥漫性撞击加速度（IA）的两个TBI模型中[18F] ASEM的PET成像特性。 1）将用[18F] ASEM -PET在CCI和TBI的IA模型中测量脑α7 -NACHR结合和分布。与其他人报道的动物和我们的初步宠物结果的动物中先前的体外α7-NACHR放射自显影数据一致，我们的假设是[18F] ASEM在TBI中的大脑特异性结合将大大降低。 [18F] ASEM特异性结合的降低将与TBI的严重程度和进展相关。 2）PET结果将通过免疫荧光染色来证实，该染色将表明TBI大鼠脑组织（在神经元和神经胶质素中）中α7-NACHR蛋白的显着改变。 该提案的实验重点是进行概念证明研究，并获得[18F] ASEM对大鼠TBI模型中PET定量α7-NACHR的适用性的证据。我们的未来目标是通过研究TBI的受体变化及其对各种治疗作用的敏感性来评估人类中TBI的潜在生物标志物。