Dissecting the roles of an epigenetic regulator of genes involved in synaptic plasticity and social cognition.

剖析涉及突触可塑性和社会认知的基因表观遗传调节剂的作用。

• 批准号: 10614039
• 负责人: Julio Licinio
• 金额: $ 72.29万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614039
• 关键词: Acetylcholine; Acute; Address; Affect; Animals; Attention deficit hyperactivity disorder; Binding; Brain Injuries; Cholinergic Receptors; Chromatin; Chronic stress; DNA Repair; Data; Development; Disease; Epigenetic Process; Fingers; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Glutamates; Goals; Grant; Hippocampus; Histone H3; Histones; Impaired cognition; Impairment; In Vitro; Learning; Manuscripts; Mediating; Memory; Memory impairment; Mental disorders; Methylation; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurons; Neuropeptides; Nicotinic Receptors; Outcome; Oxytocin; Oxytocin Receptor; Plants; Process; Proteins; RNA Splicing; Reader; Regulator Genes; Reporting; Research; Role; Schizophrenia; Short-Term Memory; Signal Transduction; Social Behavior; Social Functioning; Social Interaction; Stroke; Synapses; Synaptic plasticity; System; Testing; Time; Transgenic Mice; Traumatic Brain Injury; Vasopressins; Wild Type Mouse; autism spectrum disorder; cholinergic; epigenetic marker; epigenetic regulation; genome-wide; histone demethylase; histone modification; homeodomain; indexing; innovation; insight; knock-down; member; memory recognition; morris water maze; mouse model; neuropathology; neuropsychiatric disorder; neuropsychiatry; neurotransmission; novel; object recognition; overexpression; pharmacologic; plant morphology; preference; protein expression; receptor; recruit; social; social cognition; translational potential; treatment strategy

PROJECT SUMMARY/ABSTRACT This proposal represents a highly innovative line of research focused on understanding the mechanism/s by which PHF21B (plant homeodomain finger protein 21B) deficiency impairs social memory. Social impairments, which may be present in multiple psychiatric disorders, are characterized by deficiencies in social functioning. Social cognitive impairments are a central feature of several neurodegenerative, neuropsychiatric, and neurodevelopmental disorders, such as autism spectrum and attention deficit hyperactivity disorder. They also frequently occur following acute brain damage after traumatic brain injury and stroke. We present conceptually novel evidence showing that PHF21B deficiency significantly impairs social memory. In the three-chamber social interaction test, the social preference index of the PHF21B deficient mice did not significantly differ, but they spent more time interacting with the new stranger than with the familiar stranger compared to wild-type mice. Therefore, their social novelty index was significantly greater than wild-type animals, suggesting social memory deficits. Social memory impairments were further confirmed using the 5-trial social memory test. Our new data also support the concept that PHF21B binds to the epigenetic marker tri-methylated Lys36 at histone H3 (H3K36me3), a histone marker associated with expressed gene bodies and recruits proteins implicated in transcription, splicing, and DNA repair. The proposed studies will interrogate the specific role(s) of PHF21B in neuronal function relevant to social behaviors, specifically in social recognition impairment. Expected outcomes are to characterize the role of PHF21B in the hippocampus and identify its target genes and regulatory mechanisms relevant to social memory. We expect that the proposed studies will provide novel insights into the cellular and molecular mechanisms underlying epigenetic changes that affect social recognition memory. The results to be generated by this project have translational potential as they may facilitate the development of novel pharmacological targets for social memory deficits.

项目概要/摘要 该提案代表了一条高度创新的研究路线，重点是理解机制 PHF21B（植物同源结构域指蛋白 21B）缺乏会损害社交记忆。社会的 多种精神疾病中可能存在的障碍，其特点是缺乏 社会功能。社会认知障碍是多种神经退行性疾病的核心特征， 神经精神和神经发育障碍，例如自闭症谱系和注意力缺陷 多动症。它们也经常发生在创伤性脑损伤后的急性脑损伤之后 和中风。我们提出了概念上新颖的证据，表明 PHF21B 缺乏会显着损害 社会记忆。在三室社交互动测试中，PHF21B的社交偏好指数 有缺陷的小鼠没有显着差异，但它们与新陌生人互动的时间比 与熟悉的陌生人相比，野生型小鼠。因此，他们的社交新颖性指数为 显着高于野生型动物，表明社会记忆缺陷。社会记忆 使用五次社会记忆测试进一步证实了损伤。我们的新数据也支持 PHF21B 与组蛋白 H3 (H3K36me3) 处的表观遗传标记三甲基化 Lys36 结合的概念， 与表达的基因体相关的组蛋白标记并招募参与转录的蛋白质， 剪接和DNA修复。拟议的研究将探讨 PHF21B 在神经元中的具体作用 与社会行为相关的功能，特别是社会认知障碍。预期结果是 表征 PHF21B 在海马中的作用并确定其靶基因和调控 与社会记忆相关的机制。我们期望拟议的研究将提供新颖的见解 研究影响社会认知的表观遗传变化的细胞和分子机制 记忆。该项目产生的结果具有转化潜力，因为它们可以促进 开发针对社会记忆缺陷的新药理学靶点。