Neuronal PARP activity in fetal alcohol spectrum disorders

胎儿酒精谱系障碍中的神经元 PARP 活性

基本信息

批准号：
10152472
负责人：
SUBHASH C. PANDEY
金额：
$ 35.43万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-20 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10152472
关键词：
Adolescence Affect Binding Birth Blood - brain barrier anatomy Brain region Brain-Derived Neurotrophic Factor Cell Differentiation process Cell Nucleus Cell Survival Cell physiology Chromatin Clinical Clinical Trials DNA Binding DNA Methylation Data Dendrites Development Developmental Gene Disease Disease model Dose Drug Targeting Enzymes Epigenetic Process Ethanol Executive Dysfunction FDA approved Fetal Alcohol Exposure Fetal Alcohol Spectrum Disorder Future Gene Expression Gene Expression Regulation Gene Silencing Genes Genetic Transcription Growth Heavy Drinking Histone H3 Human Impaired cognition Impairment In Vitro Incubated Intellectual functioning disability Life Lysine Measures Medial Mediating Memory impairment Mitotic Molecular Neonatal Neonatal Alcohol Exposure Neurons PPAR gamma Pathway interactions Pharmacology Poly Adenosine Diphosphate Ribose Poly(ADP-ribose) Polymerases Post-Translational Protein Processing Prefrontal Cortex Pregnancy Proteins Proto-Oncogene Proteins c-myc Rattus Regulator Genes Role Short-Term Memory Third Pregnancy Trimester Vertebral column alcohol effect alcohol exposure c-myc Genes density executive function fetal gene repression histone demethylase in vivo inhibitor/antagonist innovation mRNA Expression neuropsychiatry overexpression poly ADP-ribose glycohydrolase postnatal prevent promoter pup transcription factor

项目摘要

Fetal alcohol spectrum disorders (FASD) are the leading known and preventable causes of intellectual disability. They impair executive functions including working memory, a function highly dependent on the medial prefrontal cortex (mPFC). This brain region is one of the last to mature, the third trimester in humans and the first 10 days after birth in rats. This is a vulnerable period for mPFC dendrites where their growth is prone to disruption from environmental insults, such as ethanol (EtOH). Poly ADP ribose polymerases (PARP) proteins are implicated in several cellular functions, including regulating gene expression. PARP synthesizes and attaches poly (ADP-ribose) (PAR) chains (PARylating) to its targets. PARP enzymes can affect gene expression by PARylating the epigenetic enzyme KDM4D. This reduces KDM4D’s ability to remove the transcriptionally repressive, dimethylated lysine 9 at histone H3 (H3K9me2). PARP-mediated gene silencing can also be accomplished by PARylating the transcription factor Peroxisome proliferator-activated receptor gamma (PPARγ). Our underlying hypothesis is that EtOH induces PARP1 activity, promoting the addition of PAR groups to known PARP1 targets such as PPARγ and KDM4D. This post-translational modification would then reduce PPARγ and KDM4D’s ability to bind DNA or chromatin resulting in changes to neurodevelopmental gene expression, dendritic arborization, and working memory. This hypothesis is supported by our preliminary data in which EtOH increased PARP activity and reduced Bdnf IV, IXa, and Klf4 mRNA expression in primary cortical neuron cultures. These changes were reversible with a PARP inhibitor. As a direct connection between PARP and PPARγ we found that PARP inhibition increased PPARγ binding to Bdnf IV and Klf4 promoters in vitro. In vivo, neonatal EtOH treatment induced PARP activity, and this coincided with a decrease in PPARγ DNA binding ability and reduced Bdnf IV mRNA expression. Thirty-one days after the final dose, the reduction in Bdnf IV expression persisted in EtOH exposed rats. In the first aim, we plan to dissect the molecular mechanisms connecting PARP to changes in developmental gene expression in the mPFC with a focus on neuron-specific changes. In order to establish the role of PARP in EtOH induced Bdnf and Klf4 gene expression silencing we will attempt to prevent expression changes by administering a PARP inhibitor ABT-888 to EtOH treated rats. We will also dissect whether PARP mediated transcriptional repression occurs via post-translational modifications to PPARγ and KDM4D using neuron cultures. In the second aim, we will establish the role of PARP in the much-replicated deficits in mPFC dendritic arborization and neuritogenesis observed in FASD models. In the third aim, we will study the role of PARP in third trimester equivalent EtOH exposure-induced spatial working memory deficits. PARP inhibitors are known to be neuroprotective, are currently undergoing clinical trials for other disorders, and cross the blood-brain barrier. Therefore, the results of these studies may be a promising avenue for future pharmacological development.

胎儿酒精谱系（FASD）是已知和可预防的遗传疾病残疾。 They impair executive functions including working memory, a function highly dependent on the 媒体前额叶皮层（MPFC）。这个大脑地区是最后一个成熟的区域之一，是人类的第三个三个月以及大鼠出生后的前10天。这是MPFC树突的脆弱时期容易受到环境侮辱的破坏，例如乙醇（ETOH）。聚ADP核糖聚合酶（PARP）蛋白质以几种细胞功能（包括调节基因表达）实现。 PARP合成并将poly（ADP-核糖）（PAR）链（Parylating）连接到其目标。 PARP酶会影响基因通过刺激表观遗传酶KDM4D的表达。这降低了KDM4D的删除能力在组蛋白H3（H3K9ME2）处的转录反射性，二甲基化的赖氨酸9。 PARP介导的基因沉默也可以通过抚养转录因子过氧化物体增生剂激活来实现受体伽马（PPARγ）。我们的基本假设是ETOH诱导PARP1活性，促进将PAR组添加到已知的PARP1靶标，例如PPARγ和KDM4D。这个后翻译然后，修改将降低PPARγ和KDM4D结合DNA或染色质的能力，从而改变神经发育基因表达，树突状树博和工作记忆。这个假设是在我们的初步数据的支持下，其中ETOH增加了PARP活性并降低了BDNF IV，IXA和KLF4 原发性皮质神经元培养物中的mRNA表达。这些变化是使用PARP抑制剂可逆的。作为PARP和PPARγ之间的直接连接，我们发现PARP抑制增加了PPARγ与 BDNF IV和KLF4启动子体外。在体内，新生儿ETOH处理诱导了PARP活性，这重合 PPARγDNA结合能力的降低并降低了BDNF IV mRNA表达。 31天后最终剂量是ETOH暴露的大鼠BDNF IV表达的降低。在第一个目标中，我们计划剖析将PARP连接到发育基因表达变化的分子机制 MPFC着重于神经特异性变化。为了确定PARP在ETOH诱导的BDNF中的作用和KLF4基因表达沉默，我们将尝试通过管理PARP来防止表达变化抑制剂ABT-888至ETOH治疗的大鼠。我们还将剖析PARP是否介导的转录表示通过使用神经元培养物对PPARγ和KDM4D的翻译后修饰发生。在第二个目标中，我们将确定PARP在MPFC树突状树皮化和在FASD模型中观察到的神经发生。在第三个目标中，我们将研究三个月中PARP的作用等效的ETOH暴露诱导的空间工作记忆定义。已知PARP抑制剂是神经保护区目前正在接受其他疾病的临床试验，并越过血脑屏障。因此，这些研究的结果可能是未来药理发展的途径。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Modulation of Poly ADP Ribose Polymerase (PARP) Levels and Activity by Alcohol Binge-Like Drinking in Male Mice.

DOI：
10.1016/j.neuroscience.2020.09.010
发表时间：
2020-11-10
期刊：
Neuroscience
影响因子：
3.3
作者：
Vallerini GP;Cheng YH;Chase KA;Sharma RP;Kusumo H;Khakhkhar S;Feinstein DL;Guizzetti M;Gavin DP
通讯作者：
Gavin DP