Elucidating the role of manganese in brain physiology and disease

背景锰（Mn）是我们饮食中的一种必需微量金属，是正常大脑功能所必需的。然而，暴露于高锰浓度会导致脑损伤和类似于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，由于受污染的饮用水和药物制剂，工业烟雾或静脉营养引起的环境和职业过度暴露，以及肝损伤患者。最近鉴定的遗传性疾病的锰运输由于异常的基因SLC30A10，SLC39A14和SLC39A8进一步突出了锰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，导致锰过载或缺乏，并且与儿童期有害的神经发育障碍相关。越来越多的证据表明，Mn失衡也是常见神经退行性疾病的特征，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，缓解上述病症的神经症状的治疗仍然不令人满意。目前可用的降低Mn水平的疗法是极其繁重的，这是由于频繁的静脉内给药需要终生、每月住院、静脉通路相关的并发症和药物副作用。因此，在这一领域的研究有很大的必要性。ii）我的研究目的本奖学金旨在建立锰在正常脑功能中的作用，并了解锰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Mn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锰转运蛋白紊乱的模型来实现。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，同时也是透明的，可以在活着的时候进行大脑成像。首先，我将通过分析大脑活动，解剖学和神经元功能来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。这将使我能够研究锰对能量代谢、自由基和细胞应激的影响，以期确定锰失衡引起的关键事件。我以前的工作已经确定了一种新的锰结合药物，有效地降低锰水平和正常化游泳活动在斑马鱼模型的锰毒性。将对该化合物和其他化合物进行生化检测，并在Mn超负荷小鼠模型中进行检测，以开发合适的儿科制剂，用于本研究之外的进一步临床前研究。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。iii）预期效益本奖学金将提供一个更好的了解锰失衡是如何参与疾病的过程中潜在的遗传性和获得性疾病与锰相关的脑损伤。这将有助于开发有效的治疗方法，以阻止疾病进展，减少患有这些疾病的儿童和成人的残疾和死亡率。识别锰在神经退行性疾病过程中的作用也可能揭示常见神经退行性疾病（如帕金森病）的疾病机制。

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.