Epigenetics of Regeneration

再生的表观遗传学

• 批准号: 10661652
• 负责人: John Andrew Watt
• 金额: $ 18.47万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-10 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10661652
• 关键词: ATAC-seq; Acetylation; Acetyltransferase; Address; Affect; Age; Anatomy; Astrocytes; Axon; Axotomy; Biological Models; Brain Injuries; Centers of Research Excellence; Central Nervous System; Central Nervous System Diseases; Chromatin; Ciliary Neurotrophic Factor; Contralateral; DNA; DNA Methylation; DNA Modification Methylases; Data Analyses; Deacetylation; Dendrites; Denervation; Development; Disease; Distant; Enzyme-Linked Immunosorbent Assay; Epigenetic Process; Event; Failure; Future; Gene Expression Profile; Genes; Genetic Transcription; Goals; Histone Deacetylase; Histones; Human; Hypothalamic structure; In Situ; Injury; Ischemia; Knowledge; Link; Measurement; Mediating; Methods; Methylation; Methyltransferase; Mixed Function Oxygenases; Modification; Natural regeneration; Nerve Degeneration; Nerve Regeneration; Neurodegenerative Disorders; Neuroglia; Neuronal Injury; Neuronal Plasticity; Neurons; Neurosecretory Systems; PIK3CG gene; Pathway interactions; Posterior Pituitary Gland; Process; Proto-Oncogene Proteins c-akt; Rattus; Recovery; Regenerative capacity; STAT3 gene; Signal Pathway; Signal Transduction; Site; System; TBI treatment; Testing; Tissues; Trauma; Traumatic Brain Injury; age related; aged; aging brain; aging population; axon growth; axonal sprouting; cell type; design; effective therapy; epigenome; epigenomics; histone acetyltransferase; histone methylation; histone methyltransferase; histone modification; in vivo; innovation; laser capture microdissection; magnocellular; neural; neuron loss; neuronal survival; novel; prevent; regeneration model; regenerative; response; tool; transcription factor; transcriptome

Epigenetics of regeneration in the aging brain PROJECT SUMMARY This project is designed to investigate the maturational decline in regenerative capability in the rat central nervous system. Our working hypothesis is that the intrinsic capacity for axon or dendritic regeneration results from an age-related alteration of epigenetic factors that regulate the organization of chromatin and accessibility of genes associated with neuronal survival and process outgrowth. This study will directly link altered transcriptome and acetylation and methylation enzymatic activity with axotomy and collateral axonal sprouting in vivo. Furthermore, we will provide the first evidence for the maturation-induced changes in the epigenetic landscape that lead to loss of neuronal plasticity in vivo. Our long term goal is to reverse age-induced alterations in the epigenetic landscape to promote neuronal survival and process outgrowth in the mature mammalian CNS. Reversal of maturation associated inhibition of regeneration will provide an important tool for promoting, regulating and directing a functionally relevant regeneration event in humans following traumatic brain injury, ischemia or neurodegenerative disease. The principle goals of this project are as follows: Aim 1: We will use an unbiased approach to compare the transcriptome and epigenomic profile in young regenerating vs aged non-regenerating hypothalamic neurons Aim 2: We will test how CNTF-induced JAK/STAT3 signaling triggers epigenetic and transcriptional events to mediate neuronal survival and axonal outgrowth. Aim 3: To determine how the PI3K-AKT pathway mediates CNTF-induced process outgrowth. In addition to applying a novel and highly relevant model system to the study of maturational changes in the SON neural and astrocyte epigenome, we propose to utilize new and innovative methods to address our specific objectives. We will take advantage of laser capture microdissection to directly assess the methylation and acetylation status of young versus mature and sprouting versus non sprouting neurons and astrocytes isolated from SON in situ. We will also interpret this data in conjunction with analysis of alterations in enzymatic activity of specific Dnmts, 5-mC hydroxylase TET activity, histone acetyltransferase, histone de-acetyltransferase and histone methyltransferase in isolated SON under similar experimental conditions.

衰老大脑再生的表观遗传学 项目摘要 本项目旨在研究大鼠中枢神经再生能力的成熟性下降 系统我们的工作假设是，轴突或树突再生的内在能力是由一个神经元引起的。 调节染色质组织和基因可及性的表观遗传因子的年龄相关改变 与神经元存活和突起生长相关。这项研究将直接将改变的转录组与 乙酰化和甲基化酶活性与轴突切断和侧支轴突发芽。此外，委员会认为， 我们将为成熟诱导的表观遗传变化提供第一个证据， 体内神经元可塑性丧失。我们的长期目标是逆转年龄引起的表观遗传改变， 景观，以促进神经元的存活和过程生长在成熟的哺乳动物中枢神经系统。逆转 成熟相关的再生抑制将提供促进、调节和 在创伤性脑损伤、局部缺血或缺血后指导人的功能相关再生事件， 神经退行性疾病该项目的主要目标如下： 目的1：我们将使用无偏的方法比较年轻人的转录组和表观基因组谱 再生与老化非再生下丘脑神经元 目的2：我们将测试CNTF诱导的JAK/STAT 3信号传导如何触发表观遗传和转录 事件介导神经元存活和轴突生长。 目的3：确定PI 3 K-AKT通路如何介导CNTF诱导的突起生长。 除了应用一个新颖的和高度相关的模型系统来研究成熟的变化， SON神经和星形胶质细胞表观基因组，我们建议利用新的和创新的方法来解决我们的 具体目标。我们将利用激光捕获显微切割直接评估甲基化 和乙酰化状态的年轻与成熟和发芽与非发芽神经元和星形胶质细胞 从SON原位分离。我们还将结合对酶活性改变的分析来解释这些数据。 特异性Dnmts活性、5-mC羟化酶泰特活性、组蛋白乙酰转移酶、组蛋白脱乙酰转移酶 和组蛋白甲基转移酶在分离的SON在类似的实验条件下。