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

FOR 2858：易位蛋白 (18 kDa) (TSPO) 作为神经系统诊断和治疗靶点的作用

• 批准号: 403161218
• 金额: --
• 依托单位: Klinik und Poliklinik für Nuklearmedizin
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/403161218?language=en
• 关键词: 2858; Role; translocator; protein; 18

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.

TSPO介导许多功能，如胆固醇转运、类固醇生成和线粒体生物能量学。此外，它在神经变性、肿瘤形成、炎症以及压力和焦虑的调节中起作用。这个跨学科的研究单位由来自大学里根斯堡，LMU慕尼黑和DZNE哥廷根的科学家组成，旨在揭示TSPO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。它分为三个科学领域。区域A涉及胶质瘤中的PET成像和伴随的组织分析，区域B致力于TSPO分子的结构和功能，而区域C关注TSPO配体的治疗潜力。在第一个资助期内，我们在A区内表明TSPO PET确实对胶质瘤患者具有预后价值，并且肿瘤和小胶质细胞都有助于TSPO PET信号。此外，我们揭示了TSPO增强胶质母细胞瘤中的免疫逃逸。在区域B内，我们获得了人TSPO的第一功率谱，并表明TSPO表达决定了多种线粒体功能。在C区内，我们检测到TSPO配体在感觉和运动神经元中发挥神经再生作用，并且这些配体保护视网膜免受损伤。此外，我们发现苯二氮卓类药物通过TSPO诱导认知下降和树突棘丢失。此外，TSPO配体在应激、焦虑和恐惧的动物模型中以性别特异性方式发挥抗焦虑作用。最后，TSPO配体差异调制神经元网络相比，苯二氮类药物在健康人的压力和焦虑的实验范式。在第二个资助期内，A区的项目旨在描述TSPO PET对胶质瘤患者长期预后和预后的预后价值，并通过放射示踪在单细胞水平上获得TSPO PET信号的分辨率。此外，将研究TSPO作为免疫治疗的潜在靶点的效用。在区域B内，我们将集中于人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表达和调节在神经变性和视网膜功能中的作用。 此外，我们还将对TSPO表达和调制在急性和慢性应激条件下的行为和神经可塑性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疾病进行第一次临床概念验证研究，以测试TSPO配体是否可以通过促进与神经元网络调制相关的内源性神经类固醇生成来构成一类新型的速效抗抑郁药。因此，在第二个资助期内，我们的目标是描绘TSPO在神经系统中的推定临床潜力。