Elucidating the role of manganese in brain physiology and disease

锰（Mn）是我们饮食中必不可少的微量金属，是正常大脑功能所必需的。然而，暴露于高浓度锰会导致脑损伤和类似帕金森病的衰弱性运动障碍。锰中毒，也称为锰中毒，发生在儿童和成人中，是由于受污染的饮用水和药物配方、工业烟雾或静脉注射营养造成的环境和职业过度暴露，也发生在肝损伤患者中。最近由于SLC30A10、SLC39A14和SLC39A8基因异常而导致的Mn转运遗传性疾病的发现，进一步凸显了Mn对脑生理的重要影响。这些疾病导致对身体锰负荷的控制受损，导致锰超载或缺乏，并与儿童有害的神经发育障碍有关。越来越多的证据表明，锰失衡也是常见神经退行性疾病的一个特征，包括帕金森病、阿尔茨海默病和亨廷顿病。我们对锰失衡如何导致疾病的理解很差，对上述情况缓解神经系统症状的治疗仍然不令人满意。由于频繁的静脉给药需要终生、每月住院、静脉通路相关的并发症和药物副作用，目前可用的降低锰水平的治疗方法非常繁重。因此，这一领域的研究是非常必要的。ii)研究目的本研究旨在确定Mn在正常脑功能中的作用，并了解Mn失衡如何干扰神经细胞内的生理过程。因此，我的工作旨在确定新的治疗靶点并改善锰相关疾病的治疗。这将通过研究已建立和验证的转基因斑马鱼作为人类Mn转运体疾病的模型来完成。斑马鱼非常适合研究神经过程，因为它们的神经系统在结构和化学上与人类相似，同时也透明，可以在活着的时候进行大脑成像。首先，我将通过对大脑活动、解剖和神经元功能的分析，确定哪些神经细胞受到Mn过载和缺乏的影响。为了更好地理解Mn失衡的影响，我将生成Mn靶向的特定神经元细胞的细胞培养模型。这将使我能够研究Mn对能量代谢、自由基和细胞应激的影响，从而确定Mn失衡引起的关键事件。我之前的工作已经确定了一种新的锰结合药物，可以有效地降低锰水平，并使锰毒性斑马鱼模型中的游泳活动正常化。该化合物和其他化合物将进行生化测试，并在Mn超载的小鼠模型中进行测试，以便开发合适的儿科配方，用于进一步的临床前研究。该项目将由我自己进行，我是一名在锰和斑马鱼研究方面具有丰富专业知识的科学家，也是一名在小鼠实验室技能方面具有丰富经验的博士后研究员。一组独特的合作者将分享斑马鱼和小鼠神经科学，细胞生物学，儿科药物开发和化学方面的世界级专业知识，确保翻译相关性。该研究将更好地了解锰失衡如何参与与锰相关脑损伤相关的遗传和获得性疾病的疾病过程。这将有助于开发有效的治疗方法，阻止疾病进展，减少患有这些疾病的儿童和成人的残疾和死亡率。确定Mn在神经退行性疾病过程中的作用也可能为帕金森病等常见神经退行性疾病的发病机制提供新的线索。

i) BackgroundManganese (Mn) is an essential trace metal in our diet that is required for normal brain function. However, exposure to high Mn concentrations causes brain damage and a debilitating movement disorder similar to Parkinson's disease. Mn toxicity, also known as manganism, occurs in children and adults upon environmental and occupational overexposure due to contaminated drinking water and drug formulations, industrial fumes or intravenous nutrition, and in patients with liver damage. The recent identification of inherited disorders of Mn transport due to abnormalities in the genes SLC30A10, SLC39A14 and SLC39A8 has further highlighted the important influence Mn has on brain physiology. These disorders lead to impaired control of the body's Mn load, resulting in Mn overload or deficiency, and are associated with detrimental neurodevelopmental disorders of childhood. There is increasing evidence that Mn imbalance is also a feature of common neurodegenerative disorders including Parkinson, Alzheimer and Huntington disease. Our understanding of how Mn imbalance leads to disease is poor and treatments to alleviate neurological symptoms for the above conditions remain unsatisfactory. Currently available therapies to lower Mn levels are extremely burdensome due to frequent intravenous administration requiring life-long, monthly hospital admissions, venous access related complications and medication side effects. Therefore, there is a great need for research in this field.ii) Aims of my researchThis fellowship intends to establish the role of Mn in normal brain function and to understand how Mn imbalance disturbs the physiological processes within nerve cells. Thereby, my work aims to identify novel therapeutic targets and improve treatments for Mn related disease. This will be accomplished through the study of established and validated genetically modified zebrafish as models for the human Mn transporter disorders. Zebrafish are ideally suited for the study of neurological processes as their nervous system is structurally and chemically similar to that of humans whilst also transparent allowing brain imaging while alive. First, I will determine which nerve cells are affected by Mn overload and deficiency through analysis of brain activity, anatomy and neuronal function. To better understand the effects of Mn imbalance I will generate cell culture models of the specific neuronal cells targeted by Mn. This will allow me to study the effect of Mn on energy metabolism, free radicals and cellular stress with a view to identifying the key events caused by Mn imbalance. My previous work has identified a novel Mn binding drug that effectively lowers Mn levels and normalises swimming activity in a zebrafish model of Mn toxicity. This and other compounds will be tested biochemically and in a mouse model of Mn overload in order to develop a suitable paediatric formulation for further preclinical studies beyond this fellowship. The project will be carried out by myself, a scientist with extensive expertise in Mn and zebrafish research, as well as a postdoctoral researcher with significant experience in mouse laboratory skills. A unique set of collaborators will share world-class expertise on zebrafish and mouse neuroscience, cell biology, paediatric drug development and chemistry ensuring translational relevance. iii) Expected benefitThis fellowship will provide a better understanding of how Mn imbalance is involved in the disease processes underlying inherited and acquired disorders associated with Mn associated brain damage. This will allow the development of effective treatments to halt disease progression and reduce disability and mortality in children and adults suffering from these disorders. Identification of the role of Mn in neurodegenerative disease processes may also shed new light on the disease mechanisms underlying common neurodegenerative disorders such as Parkinson's disease.