Nuclear sphingosine kinase 2 in Huntington disease

亨廷顿病中的核鞘氨醇激酶 2

• 批准号: 10414986
• 负责人: Andrey Tsvetkov
• 金额: $ 37.24万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10414986
• 关键词: Abbreviations; Animal Cancer Model; Animal Model; Anxiety; Apoptosis; Binding; Biochemical; Biological; Blood - brain barrier anatomy; Brain; Cell Nucleus; Cell Survival; Cells; Cessation of life; ChIP-seq; Cholesterol Homeostasis; Complex; Corpus striatum structure; Data; Disease; Disease Progression; Ectopic Expression; Female; Genes; Genetic; Genetic Transcription; Health; Heat-Shock Response; Histone Deacetylase; Huntington Disease; Huntington gene; Huntington protein; Inclusion Bodies; Inflammation; Lead; Link; Lipids; Methods; Microscopy; Modeling; Molecular; Motor; Mus; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurons; Neuroprotective Agents; Nuclear; Paper; Pathogenicity; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phenocopy; Proteins; Psyche structure; Publishing; Rodent; Role; Rotarod Performance Test; Sampling; Sepsis; Signal Pathway; Signal Transduction; Sphingosine; Symptoms; Testing; Therapeutic; Transcription Repressor; Zinc Fingers; base; behavioral outcome; cohort; disability; disease phenotype; drug discovery; field study; improved; inhibitor; male; motor symptom; mouse model; mutant; neuronal survival; neurotoxicity; novel; novel therapeutic intervention; overexpression; polyglutamine; sex; sphingosine 1-phosphate; sphingosine kinase; therapeutic target; transcription factor; transcriptome sequencing

Huntington’s disease (HD) is one of nine incurable neurodegenerative disorders caused by pathogenic polyglutamine (polyQ) expansions. Although each polyQ neurodegenerative disease develops via distinct genetic, molecular and cellular mechanisms, a feature common to all of them is transcriptional dysregulation. PolyQ-expanded proteins interact abnormally with transcriptional factors and disrupt transcription leading to neurotoxicity. Thus, normalizing transcription is a therapeutic strategy for HD and for polyQ disorders in general. A novel neuronal nuclear pathway, the sphingosine kinase 2 (SK2) pathway, regulates transcription by modulating transcription factors. In our recent paper, we demonstrated that overexpressed SK2 is toxic to neurons. We discovered that SK2 is hyperphosphorylated in brain samples from a mouse model of HD, the BACHD mice, indicating its increased activity. In our preliminary data, we also discovered a potential new binding partner of SK2 − ZHX2, zinc fingers and homeoboxes 2 transcriptional repressor. The ectopic expression of ZHX2 in primary neurons is also toxic. Remarkably, ZHX2 levels are increased in brain samples from the BACHD mice. We hypothesize that SK2/ZHX2 is a component of the pathogenic mechanisms in HD and that inhibiting SK2/ZHX2 signaling will promote survival of HD neurons. In the first aim, we will characterize the SK2/ZHX2 pathway in primary neurons. In the second aim, we will define the role of SK2/ZHX2 in HD. We recently demonstrated that an inhibitor of SK2 improves neuronal survival in two rodent neuron models of HD. Therefore, in the third aim, we will determine if inhibiting or downregulating SK2 alleviates disease phenotypes in HD mice. These studies could form the basis for SK2/ZHX2 pathway–based drug discovery, with applications to the polyQ disorders.

亨廷顿病(HD)是由致病因素引起的九种无法治愈的神经退行性疾病之一 聚谷氨酰胺(PolyQ)膨胀。尽管每一种多Q神经退行性疾病都是通过不同的 遗传、分子和细胞机制，所有这些机制的一个共同特征是转录失调。 多聚Q扩展蛋白与转录因子异常相互作用并扰乱转录，导致 神经毒性。因此，使转录正常化是治疗HD和多Q障碍的一种策略。 将军。一种新的神经核途径，鞘氨醇激酶2(SK2)途径，通过 调节转录因子。在我们最近的论文中，我们证明了过度表达的SK2对 神经元。我们发现SK2在HD小鼠模型的大脑样本中被过度磷酸化， BACHD小鼠，表明其活性增加。在我们的初步数据中，我们还发现了一个潜在的新的 −ZHX2的结合伙伴，锌指和同源异型盒2转录抑制因子。《异端》 ZHX2在原代神经元中的表达也是有毒的。值得注意的是，ZHX2在大脑样本中的水平增加 来自BACHD小鼠。我们推测SK2/ZHX2是HD发病机制的一个组成部分。 抑制SK2/ZHX2信号通路将促进HD神经元的存活。在第一个目标中，我们将 研究初级神经元中SK2/ZHX2通路的特征。在第二个目标中，我们将定义 SK2/ZHX2高清。我们最近证实，SK2的一种抑制剂可以提高两种啮齿动物的神经元存活率 HD的神经元模型。因此，在第三个目标中，我们将确定是否抑制或下调SK2 减轻HD小鼠的疾病表型。这些研究为基于SK2/ZHX2通路的研究奠定了基础 药物发现，以及在多项智力障碍方面的应用。