Molecular Basis of Mammalian Manganese Homeostasis

金属对人类健康至关重要，但过量可能有毒。我们对金属稳态的理解主要源于对金属缺乏和过量遗传疾病的研究。相对于其他金属，锰（Mn）稳态的分子基础知之甚少，因为遗传的锰相关疾病直到最近才被发现。2012年，一种金属输出蛋白SLC30A10突变在锰过量、肝脏和神经系统疾病、红细胞计数增加和促红细胞生成素过量的患者中被报道。锰过量归因于胆道锰排泄受损，而肝脏、神经系统和血液系统缺陷归因于锰毒性。利用我们在哺乳动物金属稳态方面的专业知识，我们最近证明，小鼠Slc30a10不仅对全身和胆道的锰排泄至关重要，而且对小肠向胃肠道管腔出口锰也至关重要（Mercadante等，J clininvest）。, 2019)。这表明SLC30A10在锰稳态中的作用比预期的更复杂，肝外器官有助于锰的排泄。在探索SLC30A10缺乏症中锰过量的机制基础时，我们还观察到，SLC30A10缺乏症小鼠在严重锰过量的情况下，反而出现了锰吸收增加的现象。我们的初步数据表明，这一令人惊讶的观察结果背后有一个多步骤模型。首先，过量的锰异常刺激肝脏表达促红细胞生成素激素。其次，过量的促红细胞生成素间接抑制激素hepcidin的表达，hepcidin是饮食铁吸收的抑制剂。第三，hepcidin缺乏导致锰吸收增加。由于hepcidin在锰稳态中的作用尚不明确，我们模型的最后一个新步骤是基于我们的观察，即在slc30a10缺陷小鼠中，药物刺激hepcidin表达会降低锰水平。我们认为SLC30A10缺乏是一种独特的病理生理背景，其中hepcidin在锰过量的发展中起着意想不到的关键作用。本课题旨在建立SLC30A10缺乏症中hepcidin与Mn吸收之间的机制联系，并探索通过刺激hepcidin表达治疗SLC30A10缺乏症及其他病症中Mn过量的药物作用。这将使用遗传、代谢、药理学、放射性同位素、饮食和显微技术来完成。这些研究将使我们不仅能够进一步建立哺乳动物锰稳态的分子基础，而且能够基于我们对锰稳态潜在机制的理解来设计锰相关疾病的治疗策略。

Metals are essential for human health yet potentially toxic in excess. Our understanding of metal homeostasis stems prominently from studies of inherited diseases of metal deficiency and excess. The molecular basis of manganese (Mn) homeostasis is poorly understood relative to other metals, given that inherited Mn-related diseases were only recently identified. In 2012, mutations in a metal export protein SLC30A10 were reported in patients with Mn excess, liver and neurologic disease, increased red blood cell counts, and erythropoietin excess. Mn excess was attributed to impaired biliary Mn excretion, while liver, neurologic, and hematologic defects were ascribed to Mn toxicity. Employing our expertise in mammalian metal homeostasis, we recently demonstrated that murine Slc30a10 is not only essential for systemic and biliary Mn excretion but also for Mn export by the small intestine into the lumen of the gastrointestinal tract (Mercadante et al., J Clin Invest., 2019). This indicates that the role of SLC30A10 in Mn homeostasis is more complicated than anticipated and that extrahepatic organs contribute to Mn excretion. In exploring the mechanistic basis of Mn excess in SLC30A10 deficiency, we also observed that Slc30a10-deficient mice develop paradoxically increased Mn absorption despite severe Mn excess. Our preliminary data suggest a multi-step model underlying this surprising observation. First, excess Mn aberrantly stimulates the liver to express the hormone erythropoietin. Second, erythropoietin excess indirectly suppresses expression of the hormone hepcidin, an inhibitor of dietary iron absorption. Third, hepcidin deficiency leads to increased Mn absorption. As a role for hepcidin in Mn homeostasis is not well-established, this last novel step in our model is based upon our observation that pharmacologic stimulation of hepcidin expression decreases Mn levels in Slc30a10-deficient mice . We propose that SLC30A10 deficiency is a unique pathophysiological context in which hepcidin plays an unexpected but pivotal role in development of Mn excess. The goal of this proposal is to establish the mechanistic link between hepcidin and Mn absorption in SLC30A10 deficiency and to explore pharmacologic stimulation of hepcidin expression as a treatment for Mn excess in SLC30A10 deficiency and other conditions. This will be accomplished using genetic, metabolic, pharmacologic, radioisotopic, dietary, and microscopic techniques. The proposed studies will enable us to not only further establish the molecular basis of mammalian Mn homeostasis but also to design therapeutic strategies for Mn-related diseases based upon our understanding of underlying mechanisms of Mn homeostasis.