Cell Signaling Dysregulation in Huntington's Disease

亨廷顿病中的细胞信号传导失调

基本信息

批准号：
10308703
负责人：
Rocio Gomez-Pastor
金额：
$ 33.91万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-15 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10308703
关键词：
Address Affect Behavioral Binding Sites Biochemical Brain Brain region CAG repeat Cell Survival Cell model Cells Cessation of life Corpus striatum structure Cyclic AMP-Dependent Protein Kinases Data Degradation Pathway Dependence Dependovirus Disease Disease Progression Energy Metabolism Exhibits Functional disorder Future Gene Expression Genes Genetic Transcription Goals Heat Losses Huntington Disease Huntington gene Huntington protein Impaired cognition Injections Intervention Knock-out Knockout Mice Lead Mediating Mitochondria Molecular Molecular Chaperones Motor Mus Nerve Degeneration Neurodegenerative Disorders Neurons Nucleic Acid Regulatory Sequences Pathologic Pathology Pathway interactions Patients Pharmacology Predisposition Process Protein Kinase Proteins Role Signal Transduction Stress Symptoms TP53 gene Tamoxifen Testing Therapeutic Time Transgenic Mice Transgenic Organisms United States Up-Regulation biological adaptation to stress cell type genetic manipulation heat shock transcription factor improved improved outcome mitochondrial dysfunction mouse model mutant neuron loss prevent programs protein aggregation restoration small hairpin RNA spatiotemporal therapeutic target transcription factor transcriptome sequencing ubiquitin-protein ligase

项目摘要

Huntington’s disease (HD) is a devastating neurodegenerative disease (ND) that affects approximately 30,000 patients in United States and for which no therapies are available. HD is characterized by massive protein aggregation, preferentially affecting medium spiny neurons (MSNs) in the striatum. Despite numerous studies addressing the importance of MSN degeneration in HD pathology, very little is known about the molecular mechanisms by which mutant huntingtin (mHTT) protein induces MSN death in HD. Recent evidence demonstrated that the essential heat shock transcription factor 1 (HSF1), responsible for the expression of stress protective proteins, is inappropriately degraded in MSNs in HD. We hypothesize that HSF1 degradation is a key pathway involved in MSN dysfunction and loss in HD and preventing its degradation may constitute a potential therapeutic approach. The goal of this proposal is to characterize the mechanism that leads to HSF1 degradation in MSNs, and determine if reversal of this process, even after onset of HD symptoms leads to improved outcomes. In Aim 1 we will test the hypothesis that inappropriate accumulation of the protein p53 in MSNs controls the expression of components of the HSF1 degradation pathway (protein kinase CK2α’ and E3 ligase Fbxw7), ultimately leading to loss of HSF1 and HD symptomology. This pathway would be preferentially activated in MSNs due to the enhanced CAG somatic instability observed in the striatum. To test this hypothesis, we will use molecular, pharmacological and genetic manipulations in primary neurons and transgenic HD mice. The expected results will reveal the mechanism/s by which MSNs become dysfunctional in HD and establish the basis for future understanding of the preferred susceptibility of MSNs to mHTT. Several studies have attempted to pharmacologically activate HSF1 as a therapeutic approach in HD, but they failed in achieving long-term benefits. We propose that preventing HSF1 degradation may be a more effective and long-lasting therapeutic strategy. In Aim 2 we will use pharmacological and genetic manipulations of CK2α’ in HD mice to prevent HSF1 degradation at different time points during disease progression. These studies will reveal the timeframe in which preventing HSF1 degradation is necessary to improve HD symptoms and consolidate CK2α’ as a potential therapeutic target for HD. Changes in HSF1, p53 and CK2 are also observed in other neurodegenerative diseases and therefore, our studies in HD may identify common HSF1 degradative mechanisms and therapeutic targets applicable to other NDs.

亨廷顿舞蹈症 (HD) 是一种毁灭性的神经退行性疾病 (ND)，影响约 30,000 人在美国，HD 患者没有可用的治疗方法，其特点是大量蛋白质。尽管有大量的研究，但聚集，优先影响纹状体中的中棘神经元（MSN）。关于 MSN 变性在 HD 病理学中的重要性，人们对分子机制知之甚少。突变亨廷顿蛋白 (mHTT) 蛋白诱导 HD 中 MSN 死亡的机制。最近的证据表明，必需的热休克转录因子 1 (HSF1) 负责 HD 中 MSN 中应激保护蛋白的表达被不当降解。 HSF1 降解是 HD 中 MSN 功能障碍和丢失的关键途径，并阻止其发生降解可能构成一种潜在的治疗方法，该提案的目的是表征导致 MSN 中 HSF1 降解的机制，并确定该过程是否逆转，即使在 HD 症状的出现会导致结果改善。在目标 1 中，我们将检验不适当的假设。 MSN 中 p53 蛋白的积累控制 HSF1 降解成分的表达途径（蛋白激酶 CK2α’ 和 E3 连接酶 Fbxw7），最终导致 HSF1 和 HD 丢失由于 CAG 体细胞增强，该通路将在 MSN 中优先激活。为了检验这一假设，我们将使用分子、药理学和遗传学方法。对原代神经元和转基因 HD 小鼠的操作预期结果将揭示其机制。 MSN 在 HD 中变得功能失调，并为未来理解首选内容奠定了基础 MSN 对 mHTT 的敏感性。几项研究试图通过药理学激活 HSF1 作为 HD 的治疗方法，但它们未能实现长期利益，我们建议防止 HSF1 降解可能是更有效的方法。在目标 2 中，我们将使用药理学和基因操作。 HD 小鼠中的 CK2α' 可防止疾病进展过程中不同时间点的 HSF1 降解。研究将揭示预防 HSF1 降解对于改善 HD 症状所必需的时间范围并巩固 CK2α’ 作为 HD 的潜在治疗靶点 HSF1、p53 和 CK2 的变化也在进行中。在其他神经退行性疾病中观察到，因此，我们对 HD 的研究可能会识别常见的 HSF1 适用于其他 ND 的降解机制和治疗靶点。