Molecular Basis of Mammalian Manganese Homeostasis

项目总结/摘要 金属对人类健康至关重要，但过量可能有毒。我们对金属监管的理解 体内金属水平的研究主要来自对金属缺乏和过量的遗传性疾病的研究。我们 对锰（Mn）体内平衡的理解受到以下事实的限制，即遗传形式的Mn过量， 这些缺陷是最近才发现的。在2012年，膜蛋白SLC 30 A10中的突变被报道， Mn过量、红细胞计数增加、肝病和帕金森样神经功能缺损的患者。 这些特征，加上我们的初步数据，小鼠Slc 30 a10缺陷概括了 人类疾病，表明SLC 30 A10对于Mn稳态是必需。我们的长期目标是建立 锰稳态的机制模型，我们可以探讨锰营养和遗传学的相互作用 健康和疾病状态下的生物学。我们的近期目标是确定SLC 30 A10的作用机制 缺乏导致疾病。这将通过三个目标来实现。第一个目标将决定 Slc 30 a10缺陷的特征-比在获得性帕金森病患者中观察到的帕金森样神经功能缺损更广泛。 Mn过量-是Mn过量的后果或表示Slc 30 a10的Mn非依赖性功能。第二 目的是确定肝脏和神经元Slc 30 a10功能对总体Mn稳态的相对贡献。 这一目标是相关的，因为肝脏和大脑功能都可能因SLC 30 A10缺乏而严重受损。的 第三个目标是探讨缺氧信号在疾病病理生理学中的作用。血液学缺陷 SLC 30 A10缺陷和我们的初步数据表明，SLC 30 A10缺陷导致上调， 在缺氧不存在下的缺氧反应基因表达。这一目标是相关的，因为缺氧信号具有 已知或推定在血液学、肝脏和神经系统疾病中的作用。总的来说，这项工作将建立 可用于治疗或预防疾病以及用于鉴定 在疾病发作之前或之后使用的诊断标记物。这些研究也将帮助我们了解 遗传变异性和营养状况有助于锰相关疾病的易感性。这笔赠款的供资 将使我们能够进行这些研究，并将代表Bartnikas博士早期研究生涯的关键一步。

PROJECT SUMMARY/ABSTRACT Metals are essential for human health yet potentially toxic in excess. Our understanding of the regulation of metal levels in the body stems prominently from studies of inherited diseases of metal deficiency and excess. Our understanding of manganese (Mn) homeostasis is limited by the fact that inherited forms of Mn excess and deficiency were only recently identified. In 2012, mutations in a membrane protein SLC30A10 were reported in patients with Mn excess, increased red blood cell counts, liver disease and Parkinson-like neurologic deficits. These characteristics, together with our preliminary data that murine Slc30a10 deficiency recapitulates the human disease, indicate that SLC30A10 is essential for Mn homeostasis. Our long-term objective is to establish a mechanistic model of Mn homeostasis with which we can explore the interplay of nutrition and genetics in Mn biology in states of health and disease. Our immediate goal is to determine the mechanisms by which SLC30A10 deficiency leads to disease. This will be accomplished in three aims. The first aim will determine if the diverse characteristics of Slc30a10 deficiency—broader than the Parkinson-like neurologic deficits observed in acquired Mn excess—are consequences of Mn excess or represent Mn-independent functions of Slc30a10. The second aim will establish the relative contribution of hepatic and neuronal Slc30a10 function to overall Mn homeostasis. This aim is relevant as both liver and brain function can be severely compromised by SLC30A10 deficiency. The third aim will interrogate the role of hypoxia signaling in disease pathophysiology. The hematologic defects of SLC30A10 deficiency and our preliminary data suggest that SLC30A10 deficiency leads to upregulation of hypoxia-responsive gene expression in the absence of hypoxia. This aim is relevant as hypoxia signaling has known or putative roles in hematologic, hepatic and neurologic disorders. Overall, this work will establish pathways of Mn homeostasis that may be exploited for treatment or prevention of disease and for identification of diagnostic markers for use before or after disease onset. These studies will also help us understand how genetic variability and nutritional status contribute to susceptibility to Mn-related disease. Funding of this grant will enable us to perform these studies and will represent a key step in Dr. Bartnikas' early research career.