Regulation of alternative splicing during epithelial-mesenchymal transition

上皮间质转化过程中选择性剪接的调节

• 批准号: 10712743
• 负责人: Chonghui Cheng
• 金额: $ 40万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10712743
• 关键词: Acceleration; Address; Administrative Supplement; Alternative Splicing; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease therapy; Automobile Driving; Award; Axon; Binding; Binding Proteins; Brain; Cells; Clinical; Dementia; Dendrites; Development; Disease; Dissociation; Double-Stranded RNA; Elements; Epithelium; Exons; Funding; Goals; Grant; In Vitro; Induced pluripotent stem cell derived neurons; Inflammation; Interferon Activation; Interferon Type I; Interferons; Introns; Lead; Maps; Mediating; Memory Loss; Mesenchymal; Microtubules; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Nuclear; Parents; Parkinsonian Disorders; Pathologic; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Physiological; Presynaptic Terminals; Process; Protein Isoforms; RNA; RNA Splicing; RNA-Binding Proteins; Regulation; Severity of illness; Site; Structure; Synapses; System; Tauopathies; Testing; Therapeutic; United States National Institutes of Health; design; genetic signature; hyperphosphorylated tau; induced pluripotent stem cell; interest; knock-down; molecular phenotype; mutant; neural; neural stimulation; neuroinflammation; novel; response; sensor; targeted treatment; tau Proteins; tau aggregation; tau-1; therapy development; transcriptome; transcriptome sequencing

PROJECT SUMMARY This application is being submitted in response to the Notice of Special Interest: Alzheimer’s-Focused Administrative Supplements for NIH Grants that are Not Focused on Alzheimer’s Disease, with Notice Number: NOT-AG-22-025. The overall goal for the funded parent award R35GM131876 is to investigate RNA binding protein-mediated alternative splicing regulation during epithelial-mesenchymal transition. Tauopathies are a diverse group of neurodegenerative diseases with varied presentations ranging from progressive memory loss to parkinsonism. A common tauopathy is Alzheimer’s Disease (AD), which is the primary cause of dementia worldwide. Tauopathies are characterized by the accumulation of intracellular neurofibrillary tangles (NFTs) composed of aggregates of hyperphosphorylated Tau protein. To date, there exists only one disease-modifying medication for AD treatment. The development of AD therapies that target Tau pathology are still in a nascent stage. Increasing evidence has shown that AD is driven by local inflammation in the brain. Recent findings implicated the type I interferon (IFN-I) response as a primary cause of neuroinflammation and synapse loss in AD. The IFN-stimulated gene signature is significantly enriched in murine AD models and correlated with clinical AD disease severity. Downregulating the neural IFN-I pathway restores pre-synaptic terminals and decreases plaque accumulation. Therefore, IFN-I constitutes a pivotal element within the neuroinflammatory network of AD and critically contributes to neuropathogenic processes. However, the mechanisms that stimulate neural IFN-I response remain elusive. Our lab recently discovered that hnRNPM, a ubiquitously expressed RNA binding protein (RBP), is critical for maintaining transcriptome integrity. We found that loss of hnRNPM promotes cryptic splicing. These cryptically spliced products further stimulate the IFN-I response. Interestingly, AD patient brains express decreased levels of hnRNPM. These results lead us to hypothesize that hnRNPM loss promotes AD through induction of cryptic splicing-mediated IFN-I response. We have designed two Specific Aims to test this hypothesis. In Aim 1, we will use iPSC-derived neurons from normal and tauopathy patients and examine whether hnRNPM loss stimulates IFN-I response due to cryptic splicing. In Aim 2, we will use patient iPSC-derived neurons and other established in vitro systems to determine whether loss of hnRNPM accelerates tauopathy-associated molecular phenotypes, including accumulation of Tau hyperphosphorylation and aggregation, and NFTs. Successful completion of these aims will help elucidate a novel mechanism of IFN-I activation in Tauopathy neurons governed by RNA dysregulation.

项目摘要 此申请是为了回应特别关注的通知：以阿尔茨海默氏症为重点 不关注阿尔茨海默病的NIH赠款的行政补充，通知编号： NOT-AG-22-025。受资助的父母奖R35 GM 131876的总体目标是研究RNA结合 上皮-间充质转化过程中蛋白质介导的可变剪接调节。 Tauopathies是一组不同的神经退行性疾病，具有不同的表现， 帕金森综合征的渐进性记忆丧失一种常见的tau蛋白病是阿尔茨海默病（AD），其是阿尔茨海默病（AD）。 全球痴呆症的主要原因。Tau病的特征是细胞内 神经元缠结（NFT）由过度磷酸化的Tau蛋白的聚集体组成。迄今为止， 只有一种疾病修饰药物用于AD治疗。靶向Tau的AD疗法的发展 病理学仍处于初级阶段。越来越多的证据表明，AD是由局部炎症驱动的， 大脑最近的研究结果表明，I型干扰素（IFN-I）反应是导致糖尿病的主要原因。 神经炎症和突触丢失。IFN-刺激的基因签名在小鼠中显著富集， AD模型与临床AD疾病严重程度相关。下调神经IFN-I通路恢复 突触前的终端和减少斑块的积累。因此，IFN-I构成了 AD的神经炎性网络，并在神经病理过程中起重要作用。但 刺激神经IFN-I应答的机制仍然是难以捉摸的。我们的实验室最近发现，hnRNPM， 广泛表达的RNA结合蛋白（RBP）对于维持转录组完整性至关重要。我们发现 hnRNPM的缺失促进了隐蔽剪接。这些秘密剪接的产物进一步刺激IFN-1 反应有趣的是，AD患者的大脑表达降低水平的hnRNPM。这些结果使我们 假设hnRNPM缺失通过诱导隐蔽剪接介导IFN-I促进AD 反应我们设计了两个特定目标来验证这一假设。在目标1中，我们将使用iPSC衍生的 从正常和tau蛋白病患者的神经元，并检查是否hnRNPM损失刺激IFN-I反应，由于 to cryptic神秘splicing剪接.在目标2中，我们将使用患者iPSC衍生的神经元和其他已建立的体外系统， 确定hnRNPM的丢失是否加速tau蛋白病相关的分子表型，包括 Tau过度磷酸化和聚集以及NFT的积累。成功完成这些目标 将有助于阐明一种新的机制，IFN-I激活Tau病神经元由RNA失调。