Alteration of tau splicing to identify and treat tauopathies

改变 tau 剪接以识别和治疗 tau 病

• 批准号: 8912294
• 负责人: Kathleen Marie Schoch
• 金额: $ 5.88万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8912294
• 关键词: Address; Adult; Aftercare; Age-Months; Antibodies; Antisense Oligonucleotide Therapy; Antisense Oligonucleotides; Appearance; Autopsy; Behavior; Behavioral; Biochemical; Cognition; Cognitive; Cognitive deficits; Deposition; Development; Disease; Disease Progression; Euthanasia; Evaluation; Exhibits; FTD with parkinsonism; Future; Health; Human; Human Pathology; Intraventricular Injections; Investigation; MAPT gene; Mediating; Mediator of activation protein; Messenger RNA; Modeling; Mus; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Pathogenesis; Pathology; Patients; Pattern; Phase; Phenotype; Pick Disease of the Brain; Progressive Supranuclear Palsy; Protein Isoforms; Proteins; RNA; RNA Splicing; Research; Saline; Staining method; Stains; Tauopathies; Technology; Testing; Therapeutic; Time; Tissues; Transgenes; Translations; Walking; age related; aged; brain tissue; corticobasal degeneration; design; effective therapy; expectation; functional disability; functional improvement; functional outcomes; human disease; human tissue; hyperphosphorylated tau; improved; interest; mRNA Expression; mouse model; novel; novel therapeutics; prevent; protein expression; public health relevance; repository; research study; tau Proteins; tau expression; tau mutation; treatment strategy

DESCRIPTION (provided by applicant): Neurodegenerative diseases typified by the intracellular accumulation of the microtubule-associated protein tau, collectively known as tauopathies, are both clinically and pathologically devastating. The neurofibrillary tangles formed by the abnormal hyperphosphorylation and deposition of tau suggests a tau- mediated mechanism of disease and, therefore, is a primary target of interest for the development of effective therapies. Interestingly, select tauopathies present with an imbalance of tau isoform deposition, exhibiting either predominant 4R or 3R tau inclusions. The overall hypothesis of this proposal is that a greater 4R:3R tau ratio induces tau pathogenesis, and splicing alterations to reduce the 4R:3R ratio will mitigate neurodegenerative deficits. We plan to use antisense oligonucleotides (ASOs) to manipulate the splicing patterns of tau to promote or prevent a diseased state in mouse models and subsequently performs a comprehensive evaluation of tau isoform expression in human tauopathy to help direct ASO-treatment strategies. Our results will be essential in implicating a greater 4R:3R tau ratio as pathogenic and identifying a novel target for the treatment of tauopathies. Aim 1 will use ASOs that decrease the 4R:3R ratio in a mouse model of FTDP-17 characterized by elevated 4R expression. Preliminary studies have shown amelioration of behavioral deficits and tau pathology when ASO treatment was initiated prior to the onset of pathology. In the proposed experiments, ASOs will be administered to aged mice to demonstrate reduced tau pathology and functional improvement following disease progression. This result will help support a 4R tau-directed therapy for 4R tauopathies. To specifically implicate a greater 4R:3R ratio as pathogenic, ASOs that drive 4R expression without changes to total tau will be used in a human tau-expressing mouse model (Aim 2). The expectation is that an increased 4R:3R ratio will induce greater hyperphosphorylated tau and biochemical tau pathology. Subsequently, Aim 3 will comprehensively examine the RNA and protein composition of 3R and 4R tau isoform expression in human tauopathies. We will analyze postmortem human tissues from tauopathies and healthy controls to investigate whether isoform-specific pathology is mediated by transcriptional or translational changes in tau isoforms. This information will help define the nature and future directions of ASO therapies for tauopathies. Upon completion of these aims, we will have determined the influence of 4R:3R tau ratio on age-related tau pathology and cognition in models of human neurodegeneration. These studies also may lend critical support for ASOs as a promising, novel therapy for 4R tauopathies.

描述(由申请人提供)：以微管相关蛋白tau在细胞内积聚为典型的神经退行性疾病，统称为tauopathies，在临床和病理上都是毁灭性的。神经原纤维缠结形成 通过tau的异常过度磷酸化和沉积，提示tau介导的疾病机制，因此，是开发有效治疗的主要靶点。有趣的是，某些tauopathy存在tau异构体沉积的不平衡，表现出主要的4R或3R tau包裹体。这一建议的总体假设是，较大的4R：3R tau比率会导致tau的发病，而通过剪接改变来降低4R：3R比率将减轻神经退行性变的缺陷。我们计划使用反义寡核苷酸(ASO)来操纵tau的剪接模式，以促进或防止小鼠模型中的疾病状态，并随后对tau异构体在人类tau病中的表达进行全面评估，以帮助指导ASO的治疗策略。我们的结果对于揭示更大的4R：3R tau比率作为致病因素以及确定治疗tauopathy的新靶点将是至关重要的。目的1将在以4R表达升高为特征的FTDP-17小鼠模型中使用ASO降低4R：3R比率。初步研究表明，当ASO治疗在病理发生之前开始时，行为缺陷和tau病理的改善。在拟议的实验中，ASOS将用于老年小鼠，以证明在疾病进展后tau病理减少和功能改善。这一结果将有助于支持4R tau定向治疗4R tau病。为了明确地暗示更大的4R：3R比率是致病的，驱动4R表达而不改变总tau的ASO将被用于人类tau表达的小鼠模型(目标2)。预期增加的4R：3R比率将导致更严重的过度磷酸化tau和生化tau病理。随后，目标3将全面检测3R和4R tau亚型在人类tauopathy中的表达的RNA和蛋白质组成。我们将分析来自tau病患者和健康对照组的死后人类组织，以调查tau亚型的转录或翻译变化是否介导了特定亚型的病理。这条信息会有帮助的 明确自闭症ASO疗法的性质和未来发展方向。在完成这些目标后，我们将确定4R：3R tau比率对人类神经变性模型中与年龄相关的tau病理和认知的影响。这些研究也可能为ASOS作为一种有前途的治疗4R tauopathy的新疗法提供关键支持。