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的是了解与氟哌啶醇反应遗传变异相关的因素。核心工作假设是反应和无反应受多巴胺 D2 受体 (Drd2) 基因网络的一致性水平调节。该研究计划包含四个具体目标。 1) 使用转录组测序确定 DBA/2J (D2)、BALB/cJ 和 LP/J (LP) 小鼠品系与 C57BL/6J 相比转录序列（纹状体）内的单核苷酸多态性 (SNP) 结构(B6) 参考应变。详细的 SNP 图谱是必要的：a) 以便将数量性状位点 (QTL) 单倍型结构与可能影响基因功能的多态性（例如基因多态性）对齐。非同义编码 SNP 和 b) 掩盖纹状体基因表达数据。 2) 询问在 1 号和 14 号染色体上发现的两个 QTL，它们已被反复证明与僵住反应相关。在aim1中获得的SNP数据将用于将这些QTL映射到高分辨率（1-2兆碱基对[Mbp]），以确认QTL单倍型结构并确定区间内的哪些基因具有匹配的非同义编码SNP预测的 QTL 单倍型。 SNP 数据还将用于掩盖纹状体基因表达数据库，以确定 QTL 区间内的哪些基因（实际上是转录本）显示出强顺式调节和菌株特异性可变剪接，以及哪些基因对 QTL 区间显示出强反式调节。 3) 确认氟哌啶醇无反应 a) 与 Drd2 基因表达网络的一致性降低相关 4)。确定目标 2 中确定的基因是否既影响强直反应又影响 Drd2 基因网络。该研究计划利用几种不同的方法对异质种群 [HS] 动物中的 QTL 进行精细定位，整合 QTL 分析、序列数据和功能基因组学、高通量 DNA 测序、使用短期选择性育种来确认 Drd2 网络一致性在氟哌啶醇反应中的作用以及使用所有可能的方法整合 QTL 和基于网络的方法，但强调病毒介导的转移RNA干扰。该项目自 1991 年以来一直由 VA Merit 系统资助；最初的项目始于这样的想法：如果人们能够理解为什么有些人非常敏感，而另一些人对典型精神安定药物引起的锥体外系症状（EPS）有本质上的抵抗力，那么应该有可能开发出一种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物，但几乎没有挑战这一基本前提。抛开氟哌啶醇反应的细节，所提出的工作将直接和间接地有助于我们了解基底神经节的功能组织以及该组织中遗传变异的程度。这些数据应该有助于了解各种神经系统疾病，包括亨廷顿病和帕金森病。 公共卫生相关性： “遗传学和氟哌啶醇反应”中描述的拟议研究解决了退伍军人管理局内外最困难的心理健康问题之一，即精神病的治疗。目前的治疗虽然通常可以有效减少阳性精神病症状（妄想、幻觉、思维障碍），但常常会导致许多不良副作用。氟哌啶醇等典型抗精神病药物的副作用是类似帕金森病的症状，并且长期使用基本上会出现永久性的不受控制的运动。氯氮平等非典型抗精神病药物的副作用包括糖尿病、体重严重增加和心律失常。拟议的研究建立在其他科学家的观察基础上，即在某些动物中，典型抗精神病药物引起的副作用要么永远不会发生，要么至少大大减少。该研究希望确定与这种反应减弱相关的遗传机制。有了这些信息，就可以设计出副作用更少的药物。我们还注意到，典型和非典型抗精神病药物都广泛用于治疗与痴呆相关的精神病和躁动。退伍军人的老年人口（数量正在急剧增加）非常容易受到抗精神病药物的不良影响；因此，治疗指数的提高对于这一人群应该具有特别的价值。最后，将获得的数据对于了解锥体外系的遗传结构具有普遍价值，这反过来又有助于我们了解 VA 人群中普遍存在的运动障碍，例如帕金森症。