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，因此需要以非侵入方式准确测量其影响。与 TBI 机械相关并适合具有诊断和预后意义的分子成像的生物靶点可以为 TBI 提供定量的非侵入性生物标志物。目前，这样的生物标志物还不存在。多项证据表明，TBI 会引发生化级联反应，从而降低大脑 α7-nAChR（烟碱乙酰胆碱受体的主要亚型之一）的密度。 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 [18F]ASEM 可以准确报告对照动物中 α7-nAChR 的分布，并且在对照动物中表现出明显的双边结合减少 (32-73%)。大鼠受控皮质冲击 (CCI) TBI 模型。目前，[18F]ASEM 是唯一在啮齿类动物和非人类灵长类动物 PET 研究中表现出优异的成像特性和高特异性结合的 α7-nAChR 放射性配体。该提案的主要目的是验证 [18F]ASEM 在两种大鼠 TBI 模型（局灶性 CCI 和弥散性冲击加速 (IA)）中的 PET 成像特性。 1) 将在大鼠 TBI 的 CCI 和 IA 模型中使用 [18F]ASEM - PET 测量大脑 α7-nAChR 结合和分布。与其他人报道的 TBI 动物体外 α7-nAChR 放射自显影数据以及我们的初步 PET 结果一致，我们的假设是 TBI 中 [18F]ASEM 的大脑特异性结合将显着减少。 [18F]ASEM 特异性结合的减少与 TBI 的严重程度和进展相关。 2) PET 结果将通过免疫荧光染色得到证实，该染色将证明 TBI 大鼠脑组织（神经元和胶质细胞）中 α7-nAChR 蛋白的显着改变。 本提案的实验重点是开展概念验证研究，并获得 [18F]ASEM 在大鼠 TBI 模型中通过 PET 定量 α7-nAChR 的适用性证据。我们未来的目标是通过研究 TBI 受体变化的过程及其对各种治疗效果的敏感性，评估 α7-nAChR 作为人类 TBI 的潜在生物标志物。