Imaging alpha7-nAChRs in Traumatic Brain Injury

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，需要准确地非侵入性地测量其影响。一个与脑外伤有机械联系的生物靶点适合于分子成像，具有诊断和预后意义，可以为脑外伤提供一个定量的非侵入性生物标记物。目前，这样的生物标记物还不存在。已有多条证据表明，脑外伤可触发一系列生化反应，降低大脑α7-nAChRs的密度，α7-nAChRs是烟碱型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断层扫描(PET)放射性示踪剂[18F]ASEM可以准确地报告α7-nAChRs在对照动物中的分布，并且在可控性皮质撞击(CCI)脑损伤模型中显示出显著的双侧结合减少(32-73%)。目前，[18F]ASEM是唯一在啮齿动物和非人灵长类PET研究中表现出良好的成像性能和高特异性结合的α7-nAChR放射性配基。这项建议的主要目的是验证[18F]ASEM在两种大鼠脑创伤模型(局灶性CCI和弥漫撞击加速(IA))中的PET成像特性。1)用[~(18)F]ASEM-PET测定脑创伤大鼠脑内α-7-nAChR的结合和分布。与前人报道的脑损伤动物的体外α7-nAChR放射自显影数据和我们的初步PET结果一致，我们的假设是脑内[18F]ASEM在脑损伤中的特异性结合将显著减少。[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得到证实，该结果将显示脑损伤大鼠脑组织(神经元和胶质细胞)中的α7-nAChR蛋白发生显著变化。这项建议的实验重点是开展概念验证研究，并获得[18F]ASEM在大鼠脑损伤模型中应用正电子发射计算机断层扫描(PET)定量检测α7-nAChRs的证据。我们未来的目标是通过研究脑损伤受体的变化过程及其对不同治疗效果的敏感性来评估α7-nAChRs作为人类脑损伤潜在生物标志物的作用。

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.