Role of IFNGR1 in reactive astrocyte activation

该项目旨在确定脑外组织中的炎症如何影响脑内神经元损伤的进展。星形胶质细胞是大脑中被称为胶质细胞的重要细胞类型。正常情况下，这些细胞提供有助于支持大脑内神经元健康的因子。然而，在某些情况下，这些细胞也可能在脑损伤和神经退行性变期间发生反应性星形细胞增生，这可能导致神经元死亡。我们对支持这些独特星形胶质细胞活动的分子机制知之甚少，但一项关键研究表明，来自小胶质细胞（大脑中的特殊吞噬细胞）的某些信号如何触发神经毒性星形胶质细胞活动。朊病毒引起致命的神经退行性疾病，影响动物和人类，目前尚无治愈方法。我们最近的数据显示，干扰素- γ受体1 （IFNGR1）在脑内响应朊病毒疾病期间发生的神经变性而诱导的反应性星形胶质细胞中高度特异性表达。我们还发现，由于肠道寄生虫感染的免疫反应，细胞因子干扰素- γ的产生可以增强这些IFNGR1+星形胶质细胞的神经毒性。因此，大脑中由朊病毒感染引起的神经元损伤会加速。其他研究表明，IFNGR1也在衰老的人类大脑以及帕金森病和阿尔茨海默病患者的星形胶质细胞中表达。这表明IFNGR1信号可能是许多病理性脑疾病中神经毒性星形胶质细胞激活的重要介质。然而，人们对IFNGR1+星形胶质细胞的确切功能及其对大脑神经元的影响知之甚少。因此，该建议旨在解决我们对IFNGR1信号在星形胶质细胞激活中的作用的理解中的重要知识空白。具体来说，我们的实验旨在验证星形胶质细胞中的ifn - γ - ifngr1信号传导是神经毒性反应性星形胶质细胞激活的重要触发因素，这导致神经元损伤加速。本项目的主要目的和假设是确定：1。是否需要小胶质源性因子来诱导和维持IFNGR1+反应性星形胶质细胞的分化状态2。INFGR1+反应性星形胶质细胞的功能星形胶质细胞特异性IFNGR1刺激是否以及如何加速大脑神经元损伤由于IFNGR1+反应性星形胶质细胞已在一系列病理性中枢神经系统疾病中被发现，对其表型的透彻理解将具有广泛的应用价值。由于调节星形胶质细胞的神经毒性活动的治疗可以帮助预防神经元损伤，因此本研究的数据可能有助于确定新的治疗方法，以抵消系统性ifn - γ反应（如对系统性/肠道病原体感染的反应）对某些神经退行性疾病进展的不利影响。这些数据也可能有助于开发新的方法来帮助抵消衰老对大脑的不利影响。

This project aims to determine how inflammation in tissues outside the brain can influence the progression of neuronal damage within the brain. Astrocytes are important types of cells in the brain known as glial cells. Normally these cells provide factors that help support the health of the neurons within the brain. However, under certain circumstances these cells can also undergo reactive astrocytosis following brain injury and during neurodegeneration, and this can lead to neuronal death. Little is known of the molecular mechanisms that underpin these distinct astrocyte activities, but a key study shows how certain signals from microglia (specialized phagocytes in the brain) can trigger neurotoxic astrocyte activity. Prions cause fatal neurodegenerative diseases that affect animals and humans to which there are no cures. Our recent data show that interferon-gamma receptor 1 (IFNGR1) is highly and specifically expressed by the reactive astrocytes that are induced in the brain in response to the neurodegeneration that occurs during prion disease. We also show production of the cytokine interferon-gamma, due to the immune response to infection with an intestinal worm parasite in the intestine, can enhance the neurotoxic profile of these IFNGR1+ astrocytes. As a consequence, the neuronal damage caused by the prion infection in the brain is accelerated. Other studies have shown that IFNGR1 is also expressed in astrocytes in the aging human brain and in patients with Parkinson's disease and Alzheimer's disease. This suggests that IFNGR1 signalling may be an important mediator of neurotoxic astrocyte activation in many pathological brain disorders. However, little is known of the precise function of IFNGR1+ astrocytes and the effects they have on the neurons in the brain. This proposal therefore aims to address the important knowledge gaps in our understanding of the role of IFNGR1 signalling in astrocyte activation. Specifically, our experiments are designed to test the hypothesis that IFN-gamma-IFNGR1 signalling in astrocytes is an important trigger of neurotoxic reactive astrocyte activation, and this leads to accelerated neuronal damage. The main aims and hypotheses of this project are to determine:1. whether microglia-derived factors are required for the induction and maintenance of IFNGR1+ reactive astrocytes in their differentiated state2. the function of INFGR1+ reactive astrocytes 3. whether and how astrocyte-specific IFNGR1-stimulation accelerates neuronal damage in the brainSince IFNGR1+ reactive astrocytes have been identified in a range of pathological CNS disorders, a thorough understanding of their phenotype will have widespread application. Since treatments that modulate the neurotoxic activities of astrocytes can help prevent neuronal damage, data from this study may help identify novel treatments to counteract the adverse effects of systemic IFN-gamma responses (such as those induced in response to systemic/intestinal pathogen infections) on the progression of some neurodegenerative disorders. These data may also aid development of novel methods to help counteract the adverse effects of aging on the brain.