Role and mechanisms of excretion in manganese neurotoxicity

锰神经毒性中排泄的作用和机制

基本信息

批准号：
10877469
负责人：
Somshuvra Mukhopadhyay
金额：
$ 38.18万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-03 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10877469
关键词：
Address Adult Affect Bile fluid Biological Assay Blood Body Burden Brain Child Clinical Clinical Trials Development Disease Dose Excretory function Executive Dysfunction Exhibits Exposure to Feces Future General Population Genetic Polymorphism Genetic Transcription Genetic Variation HIF1A gene Hepatic High Prevalence Human Individual Inherited Intestines Knock-in Knock-in Mouse Knock-out Knockout Mice Knowledge Life Liver Liver diseases Manganese Mediating Metals Microscopy Modeling Molecular Motor National Institute of Environmental Health Sciences Neurotransmitters Occupational Exposure Oral Organ Organism Outcome Parkinsonian Disorders Pathway interactions Patients Phase Play Population Regimen Reporting Research Risk Role Single Nucleotide Polymorphism Source Testing Therapeutic Tissues Toxic effect Up-Regulation Variant Work drinking water epidemiology study exposed human population gastrointestinal system human model insight loss of function loss of function mutation mind control motor disorder nervous system disorder neurobehavioral neurotoxic neurotoxicity novel novel therapeutic intervention prevent protective effect response therapeutically effective

项目摘要

ABSTRACT Manganese (Mn) is an essential metal, but elevated levels induce severe neurotoxicity that has no treatment. While the direct neurotoxic effects of Mn are well studied, Mn is predominantly excreted by the liver and intestines, and a high prevalence of neurotoxicity associated with elevated blood and brain Mn levels is reported in patients with liver disease. Moreover, recent epidemiological studies suggest that alterations in Mn excretory capacity are widely prevalent in the general population due to common genetic polymorphisms. Yet, the role of Mn excretion in modulating the outcomes of Mn induced neurological disease is unclear, and the critical question of whether the risk of Mn neurotoxicity depends on Mn excretion capacity has not been answered. Until recently, a major limitation in studying the relationship between Mn excretion and neurotoxicity was that the mechanisms of Mn excretion were unknown. Our recent work, supported by a NIEHS “ONES” R01, revealed that the combined activities of two Mn transporters, SLC30A10 and SLC39A14, were necessary for Mn excretion — SLC39A14 transported Mn from blood into the liver and intestines, and SLC30A10 excreted the intracellular Mn into bile and feces. Further, our analyses of Slc30a10 and/or Slc39a14 knockout mice demonstrated that brain Mn levels were primarily regulated by the excretory activities of these transporters in the liver and intestines. Based on the predominant role of excretion in controlling Mn levels in the brain, we hypothesize that hepatic and intestinal Mn excretion are critical modulators of the risks and outcomes of Mn neurotoxicity. We will test this hypothesis by leveraging liver or intestine specific Slc30a10 knockout or knockin mice, which we generated in the ONES phase, as novel human relevant models to decrease or increase Mn excretion, respectively. Aims 1 & 2 will directly establish the regulatory role of hepatic and intestinal Mn excretion in Mn neurotoxicity. In Aim 1, we will determine whether liver or intestine specific Slc30a10 knockout mice exhibit heightened sensitivity to Mn neurotoxicity. In Aim 2, we will test whether liver or intestine specific Slc30a10 knockin mice are protected against Mn neurotoxicity. Studies in Aim 2 have high translational relevance as they may identify increasing Mn excretion to be an effective strategy for the management of Mn neurotoxicity. Aim 3 will build on our finding that elevated Mn exposure enhanced SLC30A10 expression via Hif1α in the liver, providing a means to increase Mn excretion during toxicity. In Aim 3, we will elucidate the mechanisms and determine whether this response protects against neurotoxicity. These studies will provide foundational information about protective responses to Mn at the organism level, which have not yet been described, and set the stage to test if Hif1α activators, in clinical trials for other diseases, can be repurposed for Mn neurotoxicity. In sum, our studies will provide fundamental insights into a central, but overlooked, aspect of Mn neurotoxicity, and aid in the development of novel therapeutic approaches for Mn induced neurological disease.

抽象的锰（MN）是必需的金属，但升高的水平诱导没有治疗的严重神经毒性。虽然MN的直接神经毒性作用很好地研究了，但MN主要超过肝脏，并且据报道，肠以及与血液和脑MN水平升高有关的神经毒性的高流行率在肝病患者中。此外，最近的流行病学研究表明，MN排泄物的变化由于常见的遗传多态性，在普通人群中的容量普遍存在。但是， MN调节MN诱导的神经系统疾病的结局的排泄尚不清楚，这是关键的问题 MN神经毒性的风险是否取决于MN极限能力。直到最近，研究MN极端与神经毒性之间关系的主要局限性是 MN排泄的机制尚不清楚。我们最近在Niehs“ Ones” R01的支持下揭示了我们的工作 Mn排泄是必须的，两个MN转运蛋白的合并活动是SLC30A10和SLC39A14 - SLC39A14从血液中运输到肝脏和肠道，SLC30A10超过细胞内 Mn进入胆汁和粪便。此外，我们对SLC30A10和/或SLC39A14敲除小鼠的分析证明了脑MN水平主要受肝脏和肠中这些转运蛋白的极端活性调节。基于排泄在控制大脑中MN水平的主要作用，我们假设肝和肠道Mn排泄是MN神经毒性风险和结果的关键调节剂。我们将测试通过利用肝脏或肠道特异性SLC30A10敲除或敲除小鼠的假设，我们产生了在那个阶段，作为新型人类相关模型，分别减少或增加了MN极端。 AIMS 1和2将直接建立肝脏和肠道Mn排泄在MN神经毒性中的调节作用。在AIM 1中，我们将确定肝脏还是肠道特异性SLC30A10敲除小鼠暴露的小鼠对MN神经毒性的敏感性。在AIM 2中，我们将测试肝脏还是肠道特异性SLC30A10敲击蛋白小鼠受到MN神经毒性的保护。 AIM 2的研究具有很高的转化相关性，因为他们可能会发现增加MN的极端策略来管理MN神经毒性。 AIM 3将基于我们发现，Mn暴露升高通过HIF1α增强了SLC30A10的表达肝脏，提供一种增加MN极端的手段。在AIM 3中，我们将阐明机制和确定这种反应是否可以保护神经毒性。这些研究将提供基础有关尚未描述并设置的生物体对MN的受保护反应的信息在其他疾病的临床试验中，HIF1α激活剂的测试阶段是否可以用于MN神经毒性。总而言之，我们的研究将为MN的中心而被忽视的方面提供基本的见解神经毒性，并有助于开发MN诱导神经系统疾病的新型治疗方法。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A genetically encoded fluorescent sensor for manganese(II), engineered from lanmodulin.

DOI：
10.1073/pnas.2212723119
发表时间：
2022-12-20
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
通讯作者：

Hepatic and intestinal manganese excretion are both required to regulate brain manganese during elevated manganese exposure.

在锰暴露升高期间，肝脏和肠道的锰排泄都是调节脑锰所必需的。

DOI：
10.1152/ajpgi.00047.2023
发表时间：
2023
期刊：
American journal of physiology. Gastrointestinal and liver physiology
影响因子：
0
作者：
Hutchens,Steven;Jursa,ThomasP;Melkote,Ashvini;Grant,StephanieM;Smith,DonaldR;Mukhopadhyay,Somshuvra
通讯作者：
Mukhopadhyay,Somshuvra