Genetics and Haloperidol Response

遗传学和氟哌啶醇反应

• 批准号: 8262617
• 负责人: ROBERT J. HITZEMANN
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8262617
• 关键词: Address; Adverse effects; Affect; Agitation; Alternative Splicing; Animals; Antipsychotic Agents; Area; Arrhythmia; Basal Ganglia; Behavior; Brain; Breeding; Catalepsy; Chromosomes, Human, Pair 1; Chronic; Clinical; Clozapine; Code; Congenic Strain; Consensus; Corpus striatum structure; DNA; DNA Sequence; Data; Databases; Delusions; Dementia; Development; Diabetes Mellitus; Disease; Dissection; Dopamine; Drug Design; Elderly; Evaluation; Event; Evolution; Funding; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Polymorphism; Genetic Structures; Genetic Variation; Genotype; Grant; Hallucinations; Haloperidol; Hand; Haplotypes; Huntington Disease; Inbred Strain; Individual; Maps; Masks; Mediating; Mental Health; Messenger RNA; Methods; Modeling; Mouse Strains; Movement; Movement Disorders; Mus; Network-based; Nucleic Acid Regulatory Sequences; Parkinson Disease; Parkinsonian Disorders; Pharmacotherapy; Phenotype; Population; Psychotic Disorders; Quantitative Trait Loci; RNA Interference; Regimen; Regulation; Research; Research Support; Resistance; Resolution; Role; Scientist; Sequence Analysis; Single Nucleotide Polymorphism; Single Nucleotide Polymorphism Map; Structure; Symptoms; System; Testing; Therapeutic Index; Transcript; Transfer RNA; Transgenic Animals; Veterans; Viral; Weight Gain; Work; atypical antipsychotic; functional genomics; gene function; improved; mouse model; nervous system disorder; public health relevance; receptor; response; trait; treatment strategy; vector

DESCRIPTION (provided by applicant): The main objective of the research supported by "Genetics and Haloperidol Response" is to understand the factors associated with the genetic variation in haloperidol-response. The core working hypothesis is that response and non-response are regulated by the coherence level of the dopamine D2 receptor (Drd2) gene network. The research plan contains four specific aims. 1) To use transcriptome sequencing to determine the single nucleotide polymorphism (SNP) structure within transcribed sequences (striatum) in the DBA/2J (D2), BALB/cJ and LP/J (LP) mouse strains as compared to the C57BL/6J (B6) reference strain. Detailed SNP maps are necessary a) in order to align quantitative trait loci (QTL) haplotype structure with polymorphisms that may affect gene function e.g. non-synonymous coding SNPs and b) to mask striatal gene expression data. 2) To interrogate two QTLs found on chromosomes 1 and 14 and which have been repeatedly shown to be associated with the catalepsy response. The SNP data obtained in aim1 will be used to map these QTLs to a high resolution (1-2 megabase pairs [Mbp]), to confirm the QTL haplotype structure and to determine which genes within the intervals have non-synonymous coding SNPs that match the predicted QTL haplotypes. The SNP data will also be used to mask striatal gene expression databases to determine which genes (actually transcripts) within the QTL intervals show strong cis-regulation and strain specific alternative splicing and which genes show strong trans-regulation to the QTL intervals. 3) To confirm that haloperidol non-response is a) associated with a decrease in the coherence of the Drd2 gene expression network 4). To determine if the genes identified in aim 2 both affect the catalepsy response and influence the Drd2 gene network.The research plan utilizes several different methods fine mapping of QTLs in heterogeneous stock [HS] animals, the integration of QTL analysis, sequence data and functional genomics, high throughput DNA sequencing, the use of short term selective breeding to confirm the role of Drd2 network coherence in haloperidol response and the integration of the QTL and network based approaches using all possible methods but emphasizing viral mediated transfer of RNA interference. This project has been funded by the VA Merit system since 1991; the original project began with the idea that if one could understand why some individuals are very sensitive and others are essentially resistant to the extrapyramidal symptoms (EPS) induced by typical neuroleptic agents, it should be possible to develop an more effective regimen of antipsychotic drug therapy. Despite the introduction of the atypical antipsychotic drugs, there has been little to challenge this basic premise. Moving away from the specifics of haloperidol response, the proposed work will contribute directly and indirectly to our understanding of the functional organization of the basal ganglia and the extent of genetic variation in this organization. This data should prove useful in understanding a wide variety of neurological disorders, including Huntington's and Parkinson's disease. PUBLIC HEALTH RELEVANCE: The proposed research described in "Genetics and Haloperidol Response" addresses one of our most difficult mental health problems both within and outside of the VA, namely the treatment of psychosis. Current treatment, while generally effective for reducing positive psychotic symptoms(delusions, hallucinations, thought disorder) frequently leads to a number of untoward side-effects. The side-effects of the typical antipsychotics such as haloperidol are Parkinson's Disease-like symptoms and with chronic use essentially permanent uncontrolled movements. The side-effects of the atypical antipsychotic drugs such as clozapine, include diabetes, severe weight gain and cardiac arrhythmias. The proposed research builds upon the observations of other scientists that in some animals, the side-effects caused by the typical antipsychotics either never occur or are at least greatly reduced. The research hopes to determine the genetic mechanisms associated with this diminished response. With this information in hand, it should be possible to design drugs with fewer side-effects. We also note that both typical and atypical antipsychotic drugs are widely used to treat the psychosis and agitation associated with dementia. The elderly population of veterans (which is dramatically increasing) is highly vulnerable to the untoward effects of the antipsychotic drugs; thus, improvements in the therapeutic index should be of particular value to this population. Finally, the data that will be obtained will be of general value in understanding the genetic structure of the extrapyramidal system which in turn will help our understanding of movement disorders that are prevalent in the VA population, such a Parkinsonism.

描述（由申请人提供）： “遗传学和氟哌啶醇反应”支持的研究的主要目标是了解与氟哌啶醇反应的遗传变异相关的因素。核心工作假设是反应和无响应受多巴胺D2受体（DRD2）基因网络的相干水平的调节。研究计划包含四个具体目标。 1）使用转录组测序来确定与C57BL/6J（B6）参考菌株相比，在DBA/2J（D2），BALB/CJ（D2），BALB/CJ和LP/J（LP）小鼠菌株中，在DBA/2J（D2），BALB/CJ和LP/J（LP）小鼠菌株中的单核苷酸多态性（SNP）结构。详细的SNP图是必要的a），以使定量性状基因座（QTL）单倍型结构与可能影响基因功能的多态性相结合，例如非同义词编码SNP和b）掩盖纹状体基因表达数据。 2）询问在染色体1和14上发现的两个QTL，并反复证明与催化剂反应有关。在AIM1中获得的SNP数据将用于将这些QTL映射到高分辨率（1-2兆巴对[MBP]），以确认QTL单倍型结构，并确定间隔内哪些基因具有与预测的QTL单倍型相匹配的非同义编码SNP。 SNP数据还将用于掩盖纹状体基因表达数据库，以确定QTL间隔内哪些基因（实际上是转录本）显示出强的顺式调节和菌株特异性替代剪接，哪些基因在QTL间隔中显示出强大的跨调节。 3）确认氟哌啶醇无反应是a）与DRD2基因表达网络4）相干性的降低相关。为了确定目标2中鉴定的基因是否会影响催化响应并影响DRD2基因网络。该研究计划采用了几种不同的方法，在异质种群[HS]动物[HS]动物中QTL的细微映射，QTL分析的整合，序列数据和功能性基因组的整合，高级dna测序，在旋转中，置于旋转的旋转，并确认置于旋转的角色，并在旋转中验证了置于旋转的角色，并在旋转中验证了旋转的培训。使用所有可能的方法进行基于QTL和网络的方法的整合，但强调病毒介导的RNA干扰转移。自1991年以来，该项目已由VA优异系统资助；最初的项目始于这样的想法：如果人们能够理解某些人非常敏感，而另一些人则基本上对典型的神经饱和剂诱导的锥体外症状（EP）具有抵抗力，那么应该有可能开发更有效的抗精神病药物治疗方案。尽管引入了非典型抗精神病药，但几乎没有挑战这一基本前提。避开了氟哌啶醇反应的细节，拟议的工作将直接和间接地促进我们对基底神经节的功能组织的理解以及该组织中遗传变异的程度。这些数据应证明可用于了解包括亨廷顿和帕金森氏病在内的各种神经系统疾病。 公共卫生相关性： “遗传学和氟哌啶醇反应”中描述的拟议研究涉及VA内外最困难的心理健康问题之一，即对精神病的治疗。当前的治疗虽然通常可有效减少阳性精神病症状（妄想，幻觉，思想障碍），但通常会导致许多不良的副作用。典型的抗精神病药（例如氟哌啶醇）的副作用是帕金森氏病的症状，并且具有长期使用本质上是永久性的不受控制的运动。非典型抗精神病药（如氯氮平）的副作用包括糖尿病，严重的体重增加和心律不齐。拟议的研究基于其他科学家的观察结果，即在某些动物中，典型的抗精神病药造成的副作用要么永远不会发生或至少大大减少。该研究希望确定与这种减少反应相关的遗传机制。有了这些信息，应该可以设计副作用较少的药物。我们还注意到，典型和非典型抗精神病药都广泛用于治疗与痴呆症相关的精神病和躁动。老年人的退伍军人人口（急剧增加）非常容易受到抗精神病药的不良影响。因此，治疗指数的改善对于该人群应该具有特殊价值。最后，将获得的数据将在理解腹膜外系统的遗传结构中具有一般价值，这反过来又将有助于我们对VA人群中普遍存在的运动障碍的理解，例如帕金森氏症。