FOR 2858: Role of translocator protein (18 kDa) (TSPO) as a diagnostic and therapeutic target in the nervous system

TSPO介导多种功能，如胆固醇转运、类固醇合成和线粒体生物能量学。此外，它还在神经退行性变、肿瘤、炎症以及调节压力和焦虑方面发挥作用。这个由雷根斯堡大学、LMU慕尼黑大学和德国国立大学的科学家组成的跨学科研究小组旨在揭示TSPO治疗神经系统疾病的生理学和病理生理学，并促进TSPO作为诊断和治疗靶点。它被组织成三个科学领域。A区用于脑胶质瘤的PET成像和相关组织分析，B区用于研究TSPO分子的结构和功能，而C区则侧重于TSPO配体的治疗潜力。在第一个资助期，我们在A区展示了TSPO PET确实对胶质瘤患者的预后有价值，肿瘤和小胶质细胞都对TSPO PET信号有贡献。此外，我们还发现TSPO增强了胶质母细胞瘤的免疫逃逸。在B区，我们获得了人TSPO的第一功率谱，表明TSPO的表达决定了线粒体的各种功能。在C区，我们检测到TSPO配体在感觉神经元和运动神经元中发挥神经再生作用，这些配体保护视网膜免受损伤。此外，我们还发现苯二氮卓类药物通过TSPO导致认知功能下降和树突棘丢失。此外，TSPO配体在压力、焦虑和恐惧的动物模型中以性别特有的方式发挥缓解焦虑的作用。最后，在健康人类的压力和焦虑的实验范式中，TSPO配体与苯二氮平相比，对神经元网络进行了不同的调节。在第二个资助期，A区的项目旨在表征TSPO PET对胶质瘤患者长期结局和预后的预后价值，并通过放射示踪手段在单细胞水平上获得TSPO PET信号的分辨率。此外，还将研究TSPO作为免疫治疗的潜在靶点的应用。在B区，我们将重点研究人类TSPO分子与诊断和治疗TSPO配体的相互作用，以及与线粒体功能相关的临床相关多态性。在C区，我们将研究TSPO的表达和调节与神经退行性变和视网膜功能的关系。此外，我们还将对TSPO在行为和神经可塑性方面的急性和慢性应激条件下的表达和调节的作用进行翻译研究。最后，我们将在抑郁症作为一种应激相关障碍进行第一次临床概念验证研究，以测试TSPO配体是否可能通过促进与神经网络调节相关的内源性神经类固醇合成来构成一类新的快速有效的抗抑郁药物。因此，在第二个资助期，我们的目标是勾勒出神经系统中TSPO的假定临床潜力。

TSPO mediates numerous functions such as cholesterol transport, steroidogenesis, and mitochondrial bioenenergetics. Moreover, it plays a role in neurodegeneration, neoplasia, inflammation, and modulation of stress and anxiety. This interdisciplinary research unit formed by scientists from the University Regensburg, the LMU Munich and the DZNE Göttingen aims to unravel the physiology and pathophysiology of TSPO for nervous system disorders and to promote TSPO as a diagnostic and therapeutic target. It is organized into three scientific areas. Area A addresses PET imaging and concomittant tissue analyses in gliomas, area B is dedicated to structure and function of the TSPO molecule, whereas area C focusses on the therapeutic potential of TSPO ligands. During the first funding period, we showed within area A that TSPO PET is indeed of prognostic value in glioma patients and that both tumor and microglia cells contribute to the TSPO PET signal. Moreover, we revealed that TSPO enhances immune escape in glioblastoma. Within area B, we obtained first power spectra of human TSPO and showed that TSPO expression determines a variety of mitochondrial functions. Within area C, we detected that TSPO ligands exert neuroregenerative effects in sensory and motoneurons and that these ligands protect against retinal damage. Moreover, we found that benzodiazepines induce cognitive decline and dendritic spine loss via TSPO. Furthermore, TSPO ligands exerted anxiolytic effects in a gender specific manner in animal models of stress, anxiety and fear. Finally, TSPO ligands differentially modulated neuronal networks when compared with benzodiazpines in an experimental paradigm of stress and anxiety in healthy humans. During the second funding period, projects in area A aim to characterize the prognostic value of TSPO PET for long-term outcome and prognosis in glioma patients and to get a resolution of TSPO PET signals at a single cell level by means of radiotracing. Moreover, the utility of TSPO as a potential target for immunotherapy will be studied. Within area B, we will focus on the interaction of the human TSPO molecule with diagnostic and therapeutic TSPO ligands and on clinically relevant polymorphisms in relation to mitochondrial function. Within area C, we will study the role of TSPO expression and modulation in relation to neurodegeneration and retinal function. Moreover, we will perform translational studies on the role of TSPO expression and modulation in acute and chronic stress conditions regarding behaviour and neuroplasticity. Finally, we will conduct a first clinical proof of concept study in depression as a stress-related disorder to test whether TSPO ligands may constitute a novel class of fast acting antidepressants by promoting endogenous neurosteroidogenesis in relation to modulation of neuronal networks. As such, during the second funding period we aim to delineate the putative clinical potential of TSPO in the nervous system.