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（一种神经系统疾病） 它与帕金森氏病（PD）具有多种病理特征。 Mn引起的 神经毒性包括酪氨酸羟化酶（Th）的表达降低，速率限制酶 在多巴胺合成和多巴胺能神经元损伤中。但是MN引起的机制 神经毒性尚未完全理解。雌激素化合物，例如他莫昔芬，A 选择性雌激素受体调节剂（SERM）已显示在MN毒性中受到保护 和PD，但他们的行动方式仍有待确定。而转录因子re1- 沉默转录因子（静止）最初被描述为神经元基因的复制品 开发过程中非神经元细胞，最近已证明它在 保护成年神经元，并激活与神经保护有关的基因。我们的 初步数据表明，MN降低了休息，而TX则增加了其在TH-中的表达 表达神经元细胞。 REST保护多巴胺能神经元免受MN神经毒性的影响 减弱MN诱导的氧化应激，注射和凋亡。这些发现表明 REST可能介导TX诱导的对多巴胺能神经元中MN毒性的神经保护作用。 因此，研究MN诱导的神经毒性和TX诱导的静止机制 保护MN毒性对于提高我们对MN神经毒性的理解至关重要 制定治疗策略来治疗与之相关的神经退行性疾病 多巴胺能神经元功能障碍。我们假设休息可以防止MN 神经毒性通过增强Th的表达以及抗氧化剂/抗凋亡基因 过氧化氢酶（CAT）和B细胞淋巴瘤2（BCL-2），并介导Tx诱导的针对MN的保护 通过基因组ERα和非基因组ERα/GPR30途径的毒性。我们的假设将进行检验 在以下特定目的中：1）测试是否对DAERMER元中的休息受到保护免受MN的保护 小鼠的神经毒性，2）研究MN诱导的静止减少的机制 通过上调TH，CAT和BCL-2和 3）测试Daergic REST是否是TX诱导的MN毒性神经保护的关键介体。 该研究的结果将提供有关静止在DAERRONAR中的作用的关键信息 功能，MN毒性和TX诱导的针对MN毒性的神经保护作用。结果也很大 为处理与Daergic损伤相关的NDS的发展做出贡献 作为锰和潜在的PD。

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.

• 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