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）：