Alternative splicing mechanism in stress.

压力下的选择性剪接机制。

• 批准号: 10381608
• 负责人: Julio Licinio
• 金额: $ 24.3万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10381608
• 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; translational therapeutics

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.

项目摘要/摘要 该提案代表了一项高度创新的研究线，重点是MRNA剪接在 慢性应激的病理生理学。慢性压力是许多神经精神病学的主要危险因素 疾病，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失调 慢性压力，导致长期神经元功能障碍并改变情绪和认知行为。 我们有新的数据，显示了长期压力的大脑中剪接因子的失调 动物。此外，我们的发现表明上游调节剪接因子在中介中的作用 突触功能。前MRNA剪接事件的失调可能导致由于 异常蛋白表达水平和具有改变功能的蛋白质同工型的表达。所以， 我们建议研究引起的神经元功能障碍的调节前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的精确作用 神经元功能和行为中的mRNA剪接元素，并阐明它们在 慢性应激。我们期望拟议的研究的结果能够为细胞和细胞提供新的见解 压力引起的神经病理学和行为的分子机制，并确定潜力 候选人为与压力相关的神经精神疾病的未来翻译治疗策略和 瘾。本申请中提出的研究将为促进我们 了解前RNA剪接事件在响应时如何保持CNS的功能完整性 慢性压力，并将告知未来与压力有关的主要抑郁症的翻译研究， 焦虑症，PTSD，精神分裂症和成瘾。

项目成果

The epigenetic reader PHF21B modulates murine social memory and synaptic plasticity-related genes.

• DOI: 10.1172/jci.insight.158081
• 发表时间: 2022-07-22
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Chin, Eunice Wm;Ma, Qi;Ruan, Hongyu;Chin, Camille;Somasundaram, Aditya;Zhang, Chunling;Liu, Chunyu;Lewis, Martin D.;White, Melissa;Smith, Tracey L.;Battersby, Malcolm;Yao, Wei-Dong;Lu, Xin-Yun;Arap, Wadih;Licinio, Julio;Wong, Ma-Li
• 通讯作者: Wong, Ma-Li