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: 10062730
• 负责人: Eun Sook Yu Lee
• 金额: $ 54.32万
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10062730
• 关键词: Adult; Adverse effects; Alzheimer' s Disease; Animal Diseases; Antioxidants; Apoptosis; Attenuated; BCL2 gene; Binding; Brain; Cells; Chronic; Clinical Research; Cognitive deficits; Data; Development; Disease; Dopamine; Enzymes; Epigenetic Process; Estradiol; Estrogen Receptor alpha; Estrogen Receptors; Experimental Models; Exposure to; Expression Profiling; Female; Foundations; Functional disorder; GPER gene; Gene Expression; Genes; Genetic Transcription; Genomics; Human; In Vitro; Inflammation; Injury; Lead; Learning; Manganese; 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; catalase; combat; dementia risk; dopaminergic neuron; estrogenic; female sex hormone; in vivo; insight; male; malignant breast neoplasm; 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 长期接触高水平的锰会导致锰中毒，这是一种神经疾病 它与帕金森氏病(PD)具有多种病理特征。锰致敏 神经毒性包括限速酶酪氨酸羟基酶(TH)的表达减少 多巴胺的合成和多巴胺能神经元的损伤。但锰诱导的致病机制 神经毒性尚不完全清楚。雌激素化合物，如他莫昔芬，a 选择性雌激素受体调节剂(SERM)对锰中毒有保护作用 和PD，但他们的行动模式仍有待建立。而转录因子Re1- 沉默转录因子(REST)最初被描述为一种神经元基因的抑制因子 非神经细胞在发育过程中，最近被证明在 保护成年神经元，并激活参与神经保护的基因。我们的 初步数据显示，锰降低了静息时间，而TX则增加了其在Th-Th中的表达。 表达神经细胞。静息对多巴胺能神经元的保护作用 减轻锰引起的氧化应激、炎症和细胞凋亡。这些发现表明， REST可能介导TX诱导的多巴胺能神经元对锰毒性的神经保护作用。 因此，探讨静息在锰诱导的神经毒性和毒副作用中的作用机制 对锰毒性的保护对于促进我们对锰神经毒性的理解和研究具有重要意义 开发治疗策略以治疗与以下相关的神经退行性疾病 多巴胺能神经元功能障碍。我们假设休息可以预防锰中毒。 增强TH和抗氧化/抗细胞凋亡基因表达的神经毒性 过氧化氢酶(CAT)和B细胞淋巴瘤2(Bcl2)，并介导TX诱导的对锰的保护作用 通过基因组ERα和非基因组ERα/GPR30途径的毒性。我们的假设将得到检验 在以下特定目标中：1)测试DAR能神经元中的休息是否对锰有保护作用 小鼠的神经毒性，2)探讨了锰引起的静息降低的机制及对小鼠的影响。 静息通过上调TH、CAT和Bc l-2的表达对锰神经毒性的保护作用 3)检测多巴胺能静息是否是TX抗锰毒性神经保护的关键介质。 这项研究的结果将为REST在DAR能神经元中的作用提供关键信息 功能、锰毒性及毒素诱导的神经保护作用。结果也极大地 有助于开发神经SERM，以治疗与DAR损伤相关的NDS，如 作为锰中毒和潜在的帕金森病。