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，需要准确地测量其非侵入性影响。一种与TBI机械相关并适合于具有诊断和预后意义的分子成像的生物靶标可以为TBI提供定量的非侵入性生物标志物。目前，这种生物标志物并不存在。多条证据表明，TBI触发生物化学级联反应，降低大脑α 7-nAChR的密度，α 7-nAChR是烟碱乙酰胆碱受体的主要亚型之一。 来自我们实验室的初步数据表明，我们的新型正电子发射断层扫描（PET）放射性示踪剂[18 F]ASEM可以准确地报告对照动物中α 7-nAChR的分布，并且它在具有受控皮质撞击（CCI）TBI模型的大鼠中表现出显著的双侧结合减少（32-73%）。目前，[18 F]ASEM是唯一一种在啮齿动物和非人灵长类动物PET研究中表现出优异成像特性和高特异性结合的α 7-nAChR放射性配体。本提案的主要目的是验证[18 F]ASEM在大鼠TBI的两种模型（局灶性CCI和弥漫性撞击加速（IA））中的PET成像特性。 1)将在大鼠TBI的CCI和IA模型中用[18 F] ASEM-PET测量脑α 7-nAChR结合和分布。与其他人报道的TBI动物的体外α 7-nAChR放射自显影数据和我们的初步PET结果一致，我们的假设是TBI中[18 F]ASEM的脑特异性结合将显著降低。[18F]ASEM特异性结合的减少将与TBI的严重程度和进展相关。 2)PET结果将通过免疫荧光染色证实，这将证明TBI大鼠脑组织（神经元和神经胶质）中α 7-nAChR蛋白的显著改变。 本提案的实验重点是进行概念验证研究，并获得[18 F]ASEM在大鼠TBI模型中通过PET定量α 7-nAChR的适用性证据。我们未来的目标是通过研究TBI中受体变化的过程及其对各种治疗效果的敏感性来评估α 7-nAChRs作为人类TBI的潜在生物标志物。