IMAGING AUTISM BIOMARKERS + RISK GENES

自闭症生物标志物风险基因成像

• 批准号: 8117635
• 负责人: Stephen J Glatt
• 金额: $ 21.99万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8117635
• 关键词: 3 year old; Address; Adopted; Adult; Affect; Age-Months; Amygdaloid structure; Animal Model; Apoptosis; Applications Grants; Autistic Disorder; Autopsy; Basal Ganglia; Base of the Brain; Behavior; Bioinformatics; Biological; Biological Markers; Biological Markers; Biostatistics Core; Bipolar Disorder; Blood; Blood Cells; Blood specimen; Brain; Brain region; Candidate Disease Gene; Categories; Cerebellum; Child; Classification Scheme; Clinical; Cohort Studies; Data; Development; Diagnosis; Diagnostic; Diagnostic Procedure; Dimensions; Disease; Down-Regulation; Drosophila genus; Early identification; Early treatment; Environmental Risk Factor; Equilibrium; Future; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Genetic Polymorphism; Genetic Risk; Goals; Growth; Hereditary Disease; Heritability; Heterogeneity; Homologous Gene; Human; Image; Individual; Infant; Intervention; Life; Light; Link; Mental disorders; Methods; Molecular Profiling; Neural Pathways; Ontology; Outcome; Pathogenesis; Pathway interactions; Patients; Pattern; Peripheral; Peripheral Blood Mononuclear Cell; Phenotype; Polymorphism Analysis; Postmortem Changes; Prefrontal Cortex; Prevention; Relative (related person); Research; Reverse Transcriptase Polymerase Chain Reaction; Risk; Sampling; Schizophrenia; Sensitivity and Specificity; Signal Transduction; Specificity; Standardization; Structure; Surveys; Symptoms; System; Temporal Lobe; Tissue Sample; Tissue-Specific Gene Expression; Tissues; Toddler; Treatment outcome; Up-Regulation; Validation; Work; autism spectrum disorder; base; behavior measurement; brain size; brain tissue; developmental disease; diagnosis evaluation; disorder control; disorder subtype; early onset; gene discovery; improved; innovation; member; neurogenesis; novel; novel therapeutics; peripheral blood; programs; tool; treatment response

This project is one of four being proposed as part of the UCSD Autism Center of Excellence. One major goal of this study is to identify, in postmortem brain tissue, distinct gene expression profiles of autism that can implicate risk genes for this highly heritable disorder. A second major goal is to identify, in circulating blood cells, a validated gene expression profile of autism that can be developed as a diagnostic tool to improve its identification and early treatment. Although autism is recognized as having a substantial genetic component, its biological basis remains unknown. Due to its high heritability, much research has focused on identifying candidate genes that influence the disorder; however, progress has been slow. In part, this may be attributable to the "single-marker" approach adopted in most prior efforts, since the etiologic complexity and heterogeneity of autism-spectrum disorders invariably thwart classification schemes relying on a single dimension to differentiate affected and unaffected children. To move beyond this single-marker approach, a major objective of the proposed project is to validate suspected risk genes for autism (e.g., genes in the apoptosis, neurogenesis, and Drosophila wingless homolog [wnf] pathways), but also to find new candidate genes by observing patterns of expression of the entire human transcriptome in eight distinct brain regions. The lack of etiologic understanding of autism has also precluded the development of biologically based diagnostic strategies. As such, the diagnosis relies solely on observable behaviors emerging during the first years of life. Yet, the advantages of a more efficient biologically based diagnostic tool for autism are numerous, and as such, another major objective of this study is to develop biologically based markers for autism. To accomplish these objectives, we will pursue five specific aims as follows: 1) Identify ubiquitous and region-specific disruptions in brain gene expression in autism; 2) Identify blood-based predictive biomarkers of early-onset autism; 3) Identify blood-based predictive biomarkers of autism treatment response; 4) Prioritize and verify the differential expression of top candidate genes in postmortem brain and peripheral blood; and 5) Integrate the results of this project with other projects within the Center. The attainment of the :specific aims outlined above will serve to validate several groups of risk genes for autism, identify a new set of potential risk genes, and validate peripheral blood-based biomarkers of the disorder, all while determining the specificity of these effects relative to other developmental disorders and to normal development. The identification of risk genes for autism should facilitate the development of novel therapeutics, while the eventual development of a biological marker system for autism would greatly enhance the efficiency of current diagnostic methods, and it likely would facilitate the search for additional etiologic factors in the disorder.

该项目是加州大学圣地亚哥分校自闭症卓越中心提出的四个项目之一。一个主要目标 这项研究的目的是在死后的脑组织中识别自闭症的不同基因表达谱， 这种高度遗传性疾病的风险基因。第二个主要目标是在循环血液中识别 细胞，一个经过验证的自闭症基因表达谱，可以作为一种诊断工具，以提高其 识别和早期治疗。虽然自闭症被认为有很大的遗传成分， 其生物学基础仍然未知。由于其高遗传性，许多研究都集中在识别 候选基因影响的障碍;然而，进展缓慢。在某种程度上，这可能是 这归因于大多数先前的努力中采用的“单一标记”方法，因为病因的复杂性和 孤独症谱系障碍的异质性总是阻碍依赖于单一 区分受影响和未受影响的儿童。为了超越这种单一标记方法， 拟议项目的主要目标是验证自闭症的可疑风险基因（例如，基因在 细胞凋亡、神经发生和果蝇无翅同源物[wnf]途径），而且还寻找新的候选者 通过观察整个人类转录组在八个不同大脑区域的表达模式来研究基因。 缺乏对自闭症病因学的了解也阻碍了基于生物学的自闭症研究的发展。 诊断策略。因此，诊断仅依赖于在第一次检查期间出现的可观察行为。 多年的生活。然而，更有效的基于生物学的自闭症诊断工具的优点是 因此，本研究的另一个主要目的是开发基于生物学的标记物， 自闭症为了实现这些目标，我们将追求以下五个具体目标：1）识别无处不在的 自闭症患者大脑基因表达的区域特异性破坏; 2）确定基于血液的预测性 早发性自闭症的生物标志物; 3）确定自闭症治疗的基于血液的预测生物标志物 4）优先考虑并验证死后脑中顶级候选基因的差异表达， 外周血;和5）将本项目的结果与中心内的其他项目相结合。的 上述具体目标的实现将有助于验证自闭症的几组风险基因， 确定一组新的潜在风险基因，并验证基于外周血的疾病生物标志物，所有 同时确定这些效应相对于其他发育障碍和正常发育障碍的特异性 发展孤独症风险基因的鉴定将促进新的 虽然自闭症生物标记系统的最终发展将大大 提高目前诊断方法的效率，这可能有助于寻找更多的 疾病的病因学因素。