Uncovering complex expression patterns in schizophrenia

揭示精神分裂症的复杂表达模式

• 批准号: 7215620
• 负责人: Karoly Mirnics
• 金额: $ 10.85万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7215620
• 关键词: Age of Onset; Autopsy; Biological; Biometry; Brain; Brain region; Cell physiology; Collection; Complementary DNA; Complex; Custom; DNA Sequence; Data; Data Set; Diagnosis; Discipline; Disease; Disease Progression; Experimental Designs; Expressed Sequence Tags; Female; Freezing; Functional disorder; GTP-Binding Proteins; Gender; Gene Expression; Gene Expression Profile; Generic Drugs; Genes; Genetic Polymorphism; Genome; Genomics; Genotype; Glutamates; Human Genome; Immunohistochemistry; Impaired cognition; In Situ Hybridization; Individual; Knowledge; Left; Legal patent; Light; Localized; Mediating; Mental disorders; Metabolic; Metabolism; Methodology; Methods; Molecular; Molecular Profiling; Neocortex; Neurobehavioral Manifestations; Neurons; Neurosciences; Neurotransmitter Receptor; Oligodendroglia; Oligonucleotide Microarrays; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Polyamines; Polymers; Population Genetics; Prefrontal Cortex; Principal Component Analysis; Procedures; Proteins; Psychotic Disorders; Recording of previous events; Reporting; Right-On; Sampling; Schizophrenia; Scientist; Sex Characteristics; Short-Term Memory; Signal Transduction; Statistical Methods; Structure; Superior temporal gyrus; Susceptibility Gene; Testing; Tissues; Transcript; Variant; Work; cDNA Arrays; cell type; follow-up; improved; interest; male; neocortical; neuroimaging; neurotransmission; postsynaptic; presynaptic; research study

DESCRIPTION (provided by applicant): My objective is to acquire advanced and working knowledge of disciplines that will help place the microarray-obtained gene expression data into a broader biological context. For a scientist interested in genomics, ideal expertise encompasses multiple neuroscience disciplines, including (but not limited to) population genetics, biostatistics and stereological assessment of the studied tissue. This additional expertise will enable me to identify complex relationships between datasets, interpret the obtained microarray data in the light of existing linkage studies, perform limited genotyping experiments on our postmortem samples and verify the uncovered gene expression changes using non-biased, stereological sampling methods. Dysfunction of the prefrontal cortex (PFC) in schizophrenia has been associated with deficits of working memory, while functional changes in the superior temporal gyrus (STG) have been related to psychosis. Furthermore, the presentation of schizophrenia across genders has been associated with differences in age of onset, symptomathology, premorbid history, neuroimaging findings, drug responsiveness and brain structure. This application is focused around two critical questions: 1) Is there a schizophrenia-related expression profile within and across different brain regions and 2) Are schizophrenia-related expression changes different across genders? In this context, we propose to test seven specific hypotheses using 3 specific aims: Aim1 Compare gene expression pattern in 12 MALE subjects with schizophrenia and matched controls across the prefrontal (PFC) and superior temporal (STG) cortices. Aim 2. Compare gene expression pattern in 12 FEMALE subjects with schizophrenia and matched controls across the prefrontal (PFC) and superior temporal (STG) cortices. Aims 1 and 2 will share the same methodology, and compare the transcriptomes: A) Using whole genome HG_U133A and B Affymetrix microarrays. B) Using custom-made, high-sensitivity polymer eDNA microarrays. These eDNA polymer arrays, involving our proprietary probes (patent application in progress) will allow us an improved and targeted assessment of many transcripts that are too sparse to be detected by the currently available microarrays. Aim 3. Verify and localize the microarray-uncovered gene expression changes to cell types A) at transcript level using in situ hybridization; B) at protein level using immunohistochemistry and C) follow up the most promising expression changes with genotyping of postmortem samples.

描述（由申请人提供）：我的目标是获取学科的先进和工作知识，这将有助于将微阵列的基因表达数据置于更广泛的生物学环境中。对于对基因组学有兴趣的科学家来说，理想的专业知识包括多个神经科学学科，包括（但不限于）人群遗传学，生物统计学和研究组织的立体评估。这一额外的专业知识将使我能够确定数据集之间的复杂关系，根据现有的链接研究来解释所获得的微阵列数据，对我们的验尸样本进行有限的基因分型实验，并使用非偏见的，立体的采样方法验证发现的基因表达变化。 精神分裂症前额叶皮层（PFC）功能障碍与工作记忆的缺陷有关，而上颞回（STG）的功能变化与精神病有关。 此外，性别跨性别的精神分裂症的表现与发作年龄，症状病学，病前病史，神经影像学发现，药物反应能力和大脑结构的差异有关。 该应用集中在两个关键问题上：1）在不同大脑区域内外，与精神分裂症相关的表达谱以及2）与精神分裂症相关的表达在各个性别之间是否有所不同？在这种情况下，我们建议使用3个特定目的检验七个特定假设：AIM1比较了12名具有精神分裂症的男性受试者的基因表达模式，并在前额叶（PFC）和上颞（STG）皮质中进行了匹配的对照。 AIM 2。比较12名具有精神分裂症的女性受试者的基因表达模式，并在前额叶（PFC）和上颞（STG）皮质中进行匹配的对照。目标1和2将共享相同的方法，并比较转录组：a）使用整个基因组HG_U133A和B affymetrix微阵列。 b）使用定制的高敏性聚合物EDNA微阵列。 这些涉及我们的专有探针（正在进行的专利申请）的EDNA聚合物阵列将使我们对许多转录本进行改进和有针对性的评估，这些转录本太稀疏，无法被当前可用的微阵列检测到。 AIM 3。使用原位杂交在转录水平上验证和定位对细胞类型的微阵列基因表达变化； b）在蛋白质水平上使用免疫组织化学和c）跟进死后样品基因分型的最有希望的表达变化。