Cocaine Addiction and Retrotransposons

可卡因成瘾和逆转录转座子

基本信息

批准号：
8534432
负责人：
Wade H Berrettini
金额：
$ 21.26万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8534432
关键词：
Adult Affect Age American Amygdaloid structure Animal Model Area Beryllium Biological Assay Blood Brain Brain Diseases Brain region Cell physiology Central Nervous System Diseases Chronic Cocaine Cocaine Dependence Cocaine Users Controlled Clinical Trials Corpus striatum structure DNA Data Daughter Detection Development Dopamine Dorsal Dropout Elements Embryonic Development Ethnic Origin Event FDA approved Gender Gene Expression Genes Genetic Genetic Transcription Genome Genomics Glutamates Goals Harvest Human Genome Individual Inherited Introns Junk DNA Lead Medial Messenger RNA Morbidity - disease rate Mosaicism Mutation Nature Nerve Neurobiology Neuronal Differentiation Neurons Nuclear Nucleus Accumbens Organism Paste substance Patients Persons Pharmaceutical Preparations Pharmacotherapy Population Prefrontal Cortex Psychotherapy Public Health RNA RNA-Directed DNA Polymerase Relapse Retrotransposon Reverse Transcriptase Polymerase Chain Reaction Rewards Risk Saliva Support Groups Synapses Testing Time Tissues Twin Studies Ventral Tegmental Area brain tissue cocaine overdose drug development frontal lobe gene function improved laser capture microdissection mortality neuroadaptation novel peer pre-clinical public health relevance reuptake sex solution hybridization transposon/insertion element treatment program

Adult Affect Age American Amygdaloid structure Animal Model Area Beryllium Biological Assay Blood Brain Brain Diseases Brain region Cell physiology Central Nervous System Diseases Chronic Cocaine Cocaine Dependence Cocaine Users Controlled Clinical Trials Corpus striatum structure DNA Data Daughter Detection Development Dopamine Dorsal Dropout Elements Embryonic Development Ethnic Origin Event FDA approved Gender Gene Expression Genes Genetic Genetic Transcription Genome Genomics Glutamates Goals Harvest Human Genome Individual Inherited Introns Junk DNA Lead Medial Messenger RNA Morbidity - disease rate Mosaicism Mutation Nature Nerve Neurobiology Neuronal Differentiation Neurons Nuclear Nucleus Accumbens Organism Paste substance Patients Persons Pharmaceutical Preparations Pharmacotherapy Population Prefrontal Cortex Psychotherapy Public Health RNA RNA-Directed DNA Polymerase Relapse Retrotransposon Reverse Transcriptase Polymerase Chain Reaction Rewards Risk Saliva Support Groups Synapses Testing Time Tissues Twin Studies Ventral Tegmental Area brain tissue cocaine overdose drug development frontal lobe gene function improved laser capture microdissection mortality neuroadaptation novel peer pre-clinical public health relevance reuptake sex solution hybridization transposon/insertion element treatment program

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项目摘要

DESCRIPTION (provided by applicant): Cocaine addiction (CA) is a common brain disorder, affecting ~ 1,000,000 adults in the US population, creating a significant public health problem because of its chronic nature and the associated morbidity and mortality. Although twin studies are consistent with an inherited component, it has been difficult to identify risk-increasing allels by studying DNA from blood or saliva. Retrotransposons (RTPs) are mobile DNA elements that are common in the human genome. In the past 5 years, data have accumulated to prove that neuronal embryogenesis is accompanied by activation of LINE1 (L1) RTPs to an unexpected degree, such that each developing neuron may accumulate multiple de novo L1 RTP genomic insertions, perhaps as many as ~80. This results in a substantial mosaicism within populations of CNS neurons. While most of these somatic de novo L1 RTP insertions will have little effect on neuronal function (perhaps because they occur in gene deserts or in large introns or in genes not required for that cell's function), some may interfere with normal neuronal activity because they have inserted into a gene needed by that particular neuron for normal function. If one or more functional L1 RTP insertion events occur early in CNS development, all the daughter neurons that derive from that neuronal precursor will also carry the L1 insertion, perhaps leading to a dysfunctional population of neurons destined to convey risk for CA. This application will leverage post-mortem brain tissue from CA patients, who have died from a cocaine overdose, and age/gender/ethnicity matched post-mortem brain tissue from controls. Laser capture microdissection will be used to harvest distinct populations of medial frontal cortex, amygdala and striatum (brain regions implicated in neuroadaptation in CA animal models). DNA from these neurons will be analyzed by high-throughput sequencing, to detect de novo L1 RTP insertions. Any de novo (not in the reference genome) L1 RTP insertion detected in a brain-expressed gene will be investigated for functional significance using standard assays of transcription. In this manner, it is expected that novel de novo somatic L1 RTP insertions, that increase risk for CA, will be discovered.

描述（由申请人提供）：可卡因成瘾（CA）是一种常见的脑部疾病，影响了美国人口约1,000,000名成年人，由于其慢性性质以及相关的发病率和死亡率，造成了重大的公共健康问题。尽管双胞胎研究与遗传成分是一致的，但很难通过研究血液或唾液的DNA来识别风险增加的Allels。逆转录座子（RTP）是人类基因组中常见的移动DNA元素。在过去的5年中，数据积累以证明神经元的胚胎发生伴随着Line1（L1）RTP的激活，因此每个发育中的神经元可能会累积多个从头L1 RTP基因组插入，也许多达〜80。这导致了中枢神经系统神经元种群中的大量镶嵌。尽管这些从头开始L1 RTP插入中的大多数对神经元功能的影响很小（也许是因为它们发生在基因沙漠，大型内含子或该细胞功能不需要的基因中），但有些可能会干扰正常的神经元活性，因为它们已插入该特定神经元所需的基因来实现正常功能。如果一个或多个功能性L1 RTP插入事件发生在中枢神经系统发育的早期，那么从该神经元前体衍生的所有女儿神经元也将带有L1插入，也许会导致致力于CA的风险的神经元功能失调。该应用将利用CA患者的验尸后脑组织，这些患者死于可卡因过量，年龄/性别/种族与对照组相匹配的验尸后脑组织。激光捕获显微解剖将用于收集内侧额叶皮质，杏仁核和纹状体的不同种群（脑部区域与CA动物模型中的神经适应有关）。这些神经元的DNA将通过高通量测序分析，以检测Novo L1 RTP插入。将研究在脑表达基因中检测到的任何从参考基因组中的L1 RTP插入，使用标准转录测定法进行功能显着性。通过这种方式，可以发现新颖的新型体细胞L1 RTP插入，从而增加CA风险。