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Alternative splicing mechanism in stress.

压力下的选择性剪接机制。

基本信息

批准号：
10196155
负责人：
Julio Licinio
金额：
$ 20.25万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10196155
关键词：
Affect Aging Alternative Splicing Animal Model Animals Anxiety Disorders Behavior Behavioral Binding Brain Ca(2+)-Calmodulin Dependent Protein Kinase Cell Nucleus Cell model Chronic stress Clinical Research Cognitive Cognitive deficits Complex Cytoplasm Cytoskeleton Data Development Elements Emotional Etiology Event Exons Foundations Frequencies Functional disorder Future Genes Glutamate Receptor Goals Grant Growth Hippocampus (Brain)Homer 1 Homologous Protein Lead Major Depressive Disorder Mediating Mental disorders Microtubule-Associated Protein 2 Molecular Morphology NMDA receptor A1 Neuraxis Neuronal Dysfunction Neuronal Plasticity Neurons Outcome Post-Traumatic Stress Disorders Probability Process Protein Isoforms Proteins RNA RNA Splicing Reporting Research Risk Factors Role Scaffolding Protein Schizophrenia Spliceosomes Stress Synapses Synaptic plasticity Testing Therapeutic addiction anxiety-like behavior behavioral phenotyping behavioral response biological adaptation to stress calmodulin-dependent protein kinase II dendrin depressive symptoms in vivo innovation insight knock-down mRNA Precursor mental state mouse model neurodevelopment neuropathology neuropsychiatric disorder neuropsychiatry neurotransmission novel overexpression postsynaptic preclinical study prevent protein complex protein expression response stress related disorder synaptic function translational study

项目摘要

PROJECT SUMMARY/ABSTRACT This proposal represents a highly innovative line of research focusing on the role of pre-mRNA splicing in the pathophysiology of chronic stress. Chronic stress is a major risk factor for many neuropsychiatric disorders, including major depressive disorder, anxiety disorder, post-traumatic stress disorder (PTSD), schizophrenia, and addiction. Neurotransmission and synaptic plasticity are known to be dysregulated by chronic stress, leading to long-term neuronal dysfunction and altered emotional and cognitive behaviors. We have novel data showing the dysregulation of splicing factors in the brains of chronically stressed animals. Furthermore, our findings indicate a role for upstream regulatory splicing factors in mediating synaptic function. Dysregulation of pre-mRNA splicing events can lead to neuronal dysfunction due to aberrant protein expression levels and expression of protein isoforms with altered functions. Therefore, we propose to investigate a regulatory pre-mRNA splicing mechanism for the neuronal dysfunction arising from chronic stress. We will do so using animal and cellular models to determine the precise roles of pre- mRNA splicing elements in neuronal function and behavior, and to elucidate how they are dysregulated in chronic stress. We expect results from the proposed studies to provide novel insights into the cellular and molecular mechanisms underlying stress-induced neuropathology and behavior, and to identify potential candidates for future translational therapeutic strategies for stress-related neuropsychiatric disorders and addiction. The studies proposed in this application will provide a strong foundation for furthering our understanding of how pre-RNA splicing events maintain the functional integrity of the CNS as it responds to chronic stress and will inform future stress-related translational studies in major depressive disorder, anxiety disorder, PTSD, schizophrenia, and addiction.

项目总结/摘要这项建议代表了一个高度创新的研究路线，重点是前体mRNA剪接的作用，慢性压力的病理生理学慢性压力是许多神经精神疾病的主要危险因素障碍，包括重度抑郁症、焦虑症、创伤后应激障碍（PTSD），精神分裂症和成瘾已知神经传递和突触可塑性被以下因素失调：慢性压力，导致长期神经元功能障碍和改变情绪和认知行为。我们有新的数据显示，在长期紧张的大脑中，动物此外，我们的研究结果表明，上游调控剪接因子在介导突触功能前mRNA剪接事件的失调可导致神经元功能障碍，异常的蛋白质表达水平和具有改变的功能的蛋白质同种型的表达。因此，我们认为，我们建议研究神经元功能障碍的调节性前mRNA剪接机制，来自慢性压力。我们将使用动物和细胞模型来确定前- mRNA剪接元件在神经元功能和行为中的作用，并阐明它们是如何在神经元中失调的。慢性压力我们希望从拟议的研究结果，以提供新的见解，细胞和应激诱导的神经病理学和行为的分子机制，并确定潜在的压力相关神经精神障碍未来转化治疗策略的候选者，成瘾本申请中提出的研究将为我们进一步研究提供坚实的基础。了解前RNA剪接事件如何维持CNS的功能完整性，因为它响应慢性压力，并将告知未来的压力相关的转化研究，在严重抑郁症，焦虑症、创伤后应激障碍、精神分裂症和成瘾。