Epigenetics of Regeneration

衰老大脑再生的表观遗传学 项目总结 该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来自于 调节染色质组织和基因可及性的表观遗传因素的年龄相关变化 与神经元存活和突起生长有关。这项研究将直接将改变的转录组和 乙酰化和甲基化在体内具有切断轴突和侧枝轴突萌发的酶活性。此外， 我们将提供第一个证据，证明成熟导致表观遗传格局的变化，从而导致 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学变化 促进成熟哺乳动物中枢神经系统神经元存活和突起生长的景观。反转 成熟相关的再生抑制将为促进、调节和 在人类创伤性脑损伤、脑缺血或脑损伤后引导功能相关的再生事件 神经退行性疾病。该项目的主要目标如下： 目标1：我们将使用一种公正的方法来比较年轻人的转录组和表观基因组图谱。 再生与老化的非再生下丘脑神经元 目的2：我们将测试CNTF诱导的JAK/STAT3信号如何触发表观遗传和转录 调节神经元存活和轴突生长的事件。 目的：探讨PI3K-AKT通路在CNTF诱导的突起生长中的作用。 除了应用一种新的和高度相关的模型系统来研究地球的成熟变化 对于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解剖技术直接评估甲基化 以及年轻与成熟、萌芽与非萌芽神经元和星形胶质细胞的乙酰化状态 与儿子在原地隔离。我们还将结合酶的变化分析来解释这些数据 特异性DNMT活性、5-MC羟基酶Tet活性、组蛋白乙酰转移酶、组蛋白去乙酰基转移酶 和组蛋白甲基转移酶在分离的SON在相似的实验条件下。

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.