Imaging alpha7-nAChRs in Traumatic Brain Injury

描述（由申请人提供）：创伤性脑损伤（TBI）是一个重大的公共卫生问题，提出了准确测量其非侵入性影响的需求。一个与TBI机制相关的生物靶点，适合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，这样的生物标志物还不存在。多种证据表明，创伤性脑损伤触发了生化级联反应，降低了脑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。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alpha7- nachr的分布，并且在控制性皮质冲击（CCI） TBI模型大鼠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动物PET研究中表现出高特异性结合的优异成像特性的alpha7-nAChR放射配体。本研究的主要目的是验证[18F]ASEM在两种大鼠TBI模型（局灶性CCI和弥漫性冲击加速（IA））中的PET成像特性。1)采用[18F]ASEM - PET检测大鼠脑损伤CCI和IA模型脑α - 7- nachr的结合和分布。与前人报道的TBI动物体外alpha7-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[18F]ASEM在TBI中的脑特异性结合将显著减少。[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证实TBI大鼠脑组织（神经元和胶质细胞）中alpha7-nAChR蛋白的显著改变。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量化alpha7- nachr的适用性的证据。我们未来的目标是通过研究TBI中受体的变化过程及其对各种治疗效果的敏感性，来评估alpha7-nAChRs作为人类TBI的潜在生物标志物。

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.