Mechanisms associated with neuroprotection from Mn-induced neurotoxicity.

与锰诱导的神经毒性的神经保护相关的机制。

• 批准号: 10415153
• 负责人: Eun Sook Yu Lee
• 金额: $ 48.45万
• 依托单位: FLORIDA AGRICULTURAL AND MECHANICAL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-10 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10415153
• 关键词: Adult; Adverse effects; Alzheimer' s disease patient; Animal Disease Models; Antioxidants; Apoptosis; Attenuated; BCL2 gene; Binding; Brain; Breast Cancer Patient; Cells; Chronic; Clinical Research; Cognitive deficits; Data; Development; Disease; Dopamine; Enzymes; Epigenetic Process; Estradiol; Estrogen Receptor alpha; Experimental Models; Exposure to; Female; Foundations; Functional disorder; GPER gene; Gene Expression; Genes; Genetic Transcription; Genomics; Human; In Vitro; Inflammation; Injury; Lead; Learning; Longevity; Manganese; Manganism; Mediating; Mediator of activation protein; Memory; Molecular; Molecular Target; Mus; Neurodegenerative Disorders; Neuroglia; Neuronal Dysfunction; Neuronal Injury; Neurons; Outcome Study; Oxidative Stress; Parkinson Disease; Pathologic; Pathway interactions; Peripheral; Pharmacology; Phenotype; Play; RE1-silencing transcription factor; Repression; Risk Factors; Role; Selective Estrogen Receptor Modulators; Signal Transduction; Symptoms; TYRP1 gene; Tamoxifen; Technology; Testing; Therapeutic; Toxic effect; Tyrosine 3-Monooxygenase; Up-Regulation; Yin-Yang; aged; beta catenin; catalase; combat; dementia risk; dopaminergic neuron; estrogenic; female sex hormone; in vivo; insight; male; nervous system disorder; neuroprotection; neurotoxicity; nigrostriatal pathway; non-genomic; novel; overexpression; promoter; protective effect; recruit; restoration; transcription factor; vector

Project Summary Chronic exposure to high levels of manganese (Mn) causes manganism, a neurological disorder which shares multiple pathological features with Parkinson's disease (PD). Mn-induced neurotoxicity includes decreased expression of tyrosine hydroxylase (TH), a rate-limiting enzyme in dopamine synthesis, and dopaminergic neuronal injury. But the mechanisms of the Mn-induced neurotoxicity are not completely understood. Estrogenic compounds, such as tamoxifen, a selective estrogen receptor modulator (SERM), have been shown to be protective in Mn toxicity and PD, but their mode of action remains to be established. While the transcription factor RE1- silencing transcription factor (REST) was initially described as a repressor of neuronal genes in non-neuronal cells during development, it has recently been shown to play a critical role in protection of adult neurons, and it activates genes that are involved in neuroprotection. Our preliminary data reveal that Mn decreased REST, whereas TX increased its expression in TH- expressing neuronal cells. REST protected dopaminergic neurons against Mn neurotoxicity by attenuating Mn-induced oxidative stress, inflammation and apoptosis. These findings indicate that REST may mediate TX-induced neuroprotection against Mn toxicity in dopaminergic neurons. Therefore, investigating the mechanisms of REST in Mn-induced neurotoxicity and TX-induced protection against Mn toxicity is critical to advance our understanding of Mn neurotoxicity and in developing therapeutic strategies to treat neurodegenerative diseases associated with dysfunction of dopaminergic neurons. We hypothesize that REST protects against Mn neurotoxicity by enhancing expression of TH, as well as the antioxidant/antiapoptotic genes catalase (CAT) and B-cell lymphoma 2 (Bcl-2), and mediates TX-induced protection against Mn toxicity via genomic ERα and nongenomic ERα/GPR30 pathways. Our hypothesis will be tested in the following specific aims: 1) Test if REST in DAergic neurons is protective against Mn neurotoxicity in mice, 2) Investigate mechanisms of Mn-induced REST reduction and the protective effects of REST against Mn neurotoxicity via upregulation of TH, CAT and Bcl-2, and 3) Test if DAergic REST is a critical mediator of TX-induced neuroprotection against Mn toxicity. The outcome of the study will provide critical information on the role of REST in DAergic neuronal function, Mn toxicity and TX-induced neuroprotection against Mn toxicity. The results also greatly contribute to the development of `neuroSERMs' to treat NDs associated with DAergic injury, such as manganism and potentially PD.

项目摘要 长期暴露于高水平的锰（Mn）会导致锰中毒，一种神经系统疾病 其与帕金森病（PD）具有多种病理特征。锰诱导 神经毒性包括酪氨酸羟化酶（TH）表达降低， 多巴胺合成和多巴胺能神经元损伤。但锰诱导的机制 神经毒性尚未完全了解。雌激素化合物，如他莫昔芬， 选择性雌激素受体调节剂（SERM），已被证明是保护锰中毒 和PD，但其作用方式仍有待确定。而转录因子RE 1- 沉默转录因子（REST）最初被描述为神经元基因的阻遏物， 最近研究表明，它在发育过程中的非神经元细胞中发挥着关键作用 保护成年神经元，并激活参与神经保护的基因。我们 初步数据显示，锰降低REST，而TX增加其在TH-1中的表达。 表达神经元细胞。REST通过抑制锰的神经毒性保护多巴胺能神经元， 减轻Mn诱导的氧化应激、炎症和凋亡。这些发现表明 REST可能介导TX诱导的多巴胺能神经元对Mn毒性的神经保护作用。 因此，研究REST在锰引起的神经毒性和TX引起的神经毒性中的作用机制， 对锰毒性的保护是至关重要的，以促进我们对锰神经毒性的理解， 开发治疗策略以治疗与以下疾病相关的神经退行性疾病： 多巴胺能神经元功能障碍。我们假设REST可以防止锰的侵害 通过增强TH的表达以及抗氧化/抗凋亡基因的神经毒性 过氧化氢酶（CAT）和B细胞淋巴瘤2（Bcl-2），并介导TX诱导的对Mn的保护作用 通过基因组ERα和非基因组ERα/GPR 30途径的毒性。我们的假设将被验证 1）测试DA能神经元中的REST是否对Mn具有保护作用 2）研究锰诱导的小鼠REST减少和锰诱导的小鼠神经毒性的机制。 REST通过上调TH、CAT和Bcl-2对Mn神经毒性的保护作用， 3)测试DA能REST是否是TX诱导的针对Mn毒性的神经保护的关键介质。 本研究的结果将提供关于REST在DA能神经元中的作用的关键信息。 功能、Mn毒性和TX诱导的针对Mn毒性的神经保护。结果也大大 有助于开发“神经SERMs”来治疗与DA能损伤相关的ND， 锰中毒和潜在的帕金森病

项目成果

Chemokine Network and Overall Survival in TP53 Wild-Type and Mutant Ovarian Cancer.

• DOI: 10.4110/in.2018.18.e29
• 发表时间: 2018-08
• 期刊: Immune network
• 影响因子: 6
• 作者: Ignacio RMC;Lee ES;Wilson AJ;Beeghly-Fadiel A;Whalen MM;Son DS
• 通讯作者: Son DS

The TGFα-EGFR-Akt signaling axis plays a role in enhancing proinflammatory chemokines in triple-negative breast cancer cells.

• DOI: 10.18632/oncotarget.25389
• 发表时间: 2018-06-29
• 期刊: Oncotarget
• 作者: Ignacio RMC;Gibbs CR;Lee ES;Son DS
• 通讯作者: Son DS

Pancreatic Cancer Related Health Disparities: A Commentary.

胰腺癌相关的健康差异：评论。

• DOI: 10.3390/cancers10070235
• 发表时间: 2018-07-18
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Scarton L;Yoon S;Oh S;Agyare E;Trevino J;Han B;Lee E;Setiawan VW;Permuth JB;Schmittgen TD;Odedina FG;Wilkie DJ
• 通讯作者: Wilkie DJ