Genetics and Haloperidol Response

描述(由申请人提供)： 这项由《遗传学与氟哌啶醇反应》支持的研究的主要目的是了解与氟哌啶醇反应的遗传变异相关的因素。核心的工作假设是，反应和无反应由多巴胺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)利用转录组测序技术检测DBA/2J(D2)、BALB/CJ和Lp/J(LP)小鼠品系与C57BL/6J(B6)参考品系的转录序列(纹状体)中的单核苷酸多态性(SNP)结构。为了将数量性状基因座(QTL)的单倍型结构与可能影响基因功能的多态(如非同义编码的SNPs)进行比对，以及为了掩盖纹状体基因表达数据，详细的SNP图谱是必要的。2)询问在1号和14号染色体上发现的两个QTL，这两个QTL已被反复证明与分类反应有关。在AIM1中获得的SNP数据将被用来将这些QTL定位到高分辨率(1-2兆碱基对[MBP])，以确认QTL单倍型结构，并确定区间内哪些基因具有与预测的QTL单倍型匹配的非同义编码SNP。SNP数据还将用于屏蔽纹状体基因表达数据库，以确定QTL区间内哪些基因(实际上是转录本)表现出强烈的顺式调控和菌株特异性的选择性剪接，以及哪些基因对QTL区间表现出强烈的反式调节。3)确认氟哌啶醇无反应是a)与DRD2基因表达网络的连贯性降低有关4)。为了确定目标2中确定的基因是否既影响目录反应又影响Drd2基因网络。研究计划使用几种不同的方法在异种动物中精细定位QTL，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，但强调强调病毒介导的RNA干扰的转移。该项目自1991年以来一直由退伍军人福利制度资助；最初的项目始于这样一个想法，即如果一个人能够理解为什么一些人非常敏感，而另一些人基本上对典型的抗精神病药物引起的锥体外系症状(EPS)具有抵抗力，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。尽管推出了非典型的抗精神病药物，但几乎没有人挑战这一基本前提。撇开氟哌啶醇反应的细节不谈，拟议的工作将直接和间接地有助于我们理解基底节的功能组织和该组织中遗传变异的程度。这些数据应该有助于了解包括亨廷顿氏症和帕金森氏症在内的多种神经系统疾病。 公共卫生相关性： 《遗传学和氟哌啶醇反应》中描述的拟议研究解决了退伍军人管理局内外最困难的精神健康问题之一，即精神病的治疗。目前的治疗方法虽然通常对减少阳性精神病症状(妄想、幻觉、思维障碍)有效，但经常会导致一些不良副作用。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，如果长期使用，基本上是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、严重体重增加和心律失常。这项拟议的研究建立在其他科学家的观察基础上，即在一些动物中，典型的抗精神病药物引起的副作用要么从未发生过，要么至少大大减少了。这项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，设计副作用更少的药物应该是可能的。我们还注意到，典型和非典型抗精神病药物都被广泛用于治疗与痴呆症相关的精神病和激越。退伍军人的老年人口(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，治疗指数的改善对这一群体应该特别有价值。最后，将获得的数据将对了解锥体外系的遗传结构具有普遍价值，这反过来将有助于我们了解在退伍军人中普遍存在的运动障碍，如帕金森氏症。

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.