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: 10446334
• 负责人: Julio Licinio
• 金额: $ 72.61万
• 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/10446334
• 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 (Brain); Histone H3; Histones; Impaired cognition; Impairment; In Vitro; Learning; Manuscripts; Mediating; Memory; Memory impairment; Mental disorders; Molecular; Morphology; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurons; Neuropeptides; Nicotinic Receptors; Outcome; Oxytocin; Oxytocin Receptor; Pharmacology; 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; 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.

项目摘要/摘要 该提案代表着一项高度创新的研究线，重点是理解机制 PHF21B（植物同源域手指蛋白21b）缺乏会损害社交记忆。社会的 可能出现多种精神疾病的障碍以缺陷为特征 社会功能。社会认知障碍是几种神经退行性的核心特征 神经精神病学和神经发育障碍，例如自闭症和注意力缺陷 多动症障碍。脑损伤后急性脑损伤后，它们也经常发生 和中风。我们提供了概念上的新证据，表明PHF21B缺乏症会严重损害 社交记忆。在三座社会互动测试中，PHF21B的社会偏好指数 缺乏小鼠没有显着差异，但是他们花了更多的时间与新陌生人互动 与熟悉的陌生人相比，与野生型小鼠相比。因此，他们的社会新颖性指数是 明显大于野生型动物，表明社会记忆缺陷。社交记忆 使用5次试验的社交记忆测试进一步证实了障碍。我们的新数据也支持 PHF21b与组蛋白H3（H3K36Me3）的表观遗传标记物三甲基化Lys36结合的概念，A 与表达基因体和募集有关转录的蛋白质相关的组蛋白标记物， 剪接和DNA修复。拟议的研究将询问PHF21B在神经元中的特定作用 与社会行为相关的功能，特别是社会识别障碍。预期的结果是 表征PHF21b在海马中的作用，并确定其靶基因和调节性 与社交记忆有关的机制。我们希望拟议的研究将提供新颖的见解 进入影响社会识别的表观遗传变化的基础和分子机制 记忆。该项目要产生的结果具有转化潜力，因为它们可能会促进 开发新型的社会记忆缺陷的药理学靶标。