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。

基本信息

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
项目类别：
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&apos 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

项目摘要

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。神经毒性包括降低酪氨酸羟化酶（TH）的表达，速率限制酶在多巴胺合成和多巴胺能神经元损伤中。神经毒性不是化合物，是他莫昔芬的性别选择性雌激素受体改装剂（SERM）和PD，但动作方式仍有待确定。沉默转录因子（静止）最初被描述为神经元基因的阻遏物开发过程中非神经元细胞，最近已证明它在我们的初步数据启示了Mn减少休息，而TX则增加了其在TH-中的表达表达神经元细胞。减弱MN诱导的氧化应激，炎症和炎症。 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诱导的静止机制防止Mn毒品的保护，以促进我们对Mn神经毒性的理解制定治疗策略以信任与之相关的神经退行性疾病多巴胺能神经元的功能障碍。神经毒性通过增强Th的表达以及抗氧化剂/抗抑制剂基因过氧化氢酶（CAT）和B细胞淋巴瘤2（BCl-2），以及介导TX诱导的对MN的保护通过基因组ERα和非基因组ERα/GPR30途径的毒性。在以下特定目的中：1）测试是否在Daergic神经元中休息是保护性MN 小鼠的神经毒性，2）研究MN诱导的休息降低的机制和您通过上调TH，CAT和BCL-2和2 3）测试Daergic REST是否是TX诱导的针对MN毒理的神经保护作用的关键介体。研究的结果提供了有关静止作用在DAERMER元中的作用的关键信息功能，MN毒剂和TX诱导的神经保护作用也很大。为处理与Daergic损伤相关的NDS的发展做出贡献作为锰和电力PD。