Coordination Funds

TSPO介导多种功能，如胆固醇转运、类固醇生成和线粒体生物能学。此外，它还在神经变性、肿瘤、炎症以及压力和焦虑的调节中发挥作用。这个跨学科的研究单位由雷根斯堡大学、慕尼黑大学和DZNE Göttingen的科学家组成，旨在揭示TSPO在神经系统疾病中的生理和病理生理学，并促进TSPO作为诊断和治疗靶点。它被组织成三个科学领域。区域A涉及胶质瘤的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侧重于TSPO配体的治疗潜力。在第一个资助期，我们在A区表明，TSPO PET确实对胶质瘤患者具有预后价值，肿瘤和小胶质细胞都参与了TSPO PET信号。此外，我们发现TSPO增强胶质母细胞瘤的免疫逃逸。在B区，我们获得了人类TSPO的第一个功率谱，并表明TSPO的表达决定了多种线粒体功能。在C区，我们发现TSPO配体在感觉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，我们发现苯二氮卓类药物通过TSPO诱导认知能力下降和树突状脊柱丢失。此外，在应激、焦虑和恐惧动物模型中，TSPO配体以性别特异性的方式发挥抗焦虑作用。最后，在健康人类压力和焦虑的实验范式中，与苯二氮平类药物相比，TSPO配体对神经网络的调节存在差异。在第二个资助期，A领域的项目旨在表征TSPO PET对胶质瘤患者长期预后和预后的预后价值，并通过放射性示踪在单细胞水平上获得TSPO PET信号的分辨率。此外，还将研究TSPO作为免疫治疗潜在靶点的效用。在区域B中，我们将重点关注人类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。在区域C中，我们将研究TSPO的表达和调节在神经变性和视网膜功能中的作用。此外，我们将对TSPO表达和调节在急性和慢性应激条件下有关行为和神经可塑性的作用进行转化研究。最后，我们将对抑郁症作为一种压力相关疾病进行首次临床概念证明研究，以测试TSPO配体是否可能通过促进内源性神经甾体生成与神经元网络调节相关而构成一类新的速效抗抑郁药。因此，在第二个资助期，我们的目标是描述神经系统中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.