Utah Autism Program

描述(由申请人提供)：这份续签申请提出了三个项目和三个核心，以扩展与自闭症相关的表型研究。免疫部分将解决四个具体目标：1)调查5-羟色胺与免疫失调之间的相互作用；2)表征自闭症患者T细胞和抗体的特异性和自身反应性；遗传部分将收集有关受影响病例和亲属的DNA和临床信息(包括中间表型、更广泛的自闭症表型、头围、5-羟色胺水平和免疫部分确定的免疫表型的存储血清)。将对已经通过犹他州人口数据库确定的五个犹他州扩展家庭进行评估，并对两个新的扩展家系进行评估，这些新的扩展家系将通过UPDB对通过调查以及州卫生部和犹他大学诊所确定的800例新的自闭症病例进行新的搜索来确定。将使用马什菲尔德哺乳动物基因分型服务进行5厘米的基因组扫描。将使用临床表型和中间表型分析家系，以绘制易感基因座图。将使用SNPs对连锁峰下和/或免疫成分识别的五个候选基因进行基因分型。DNA、全血(用于未来的5-羟色胺)和血清(用于未来的免疫表型)将储存在800例新的自闭症患者及其父母身上，用于未来基于家庭的关联研究。神经成像部分将研究自闭症患者，利用结构和功能成像研究来解决以下具体目标：1)描述大脑体积结构的纵向变化及其与临床表型变化的关系；2)描述大脑结构、白质结构和完整性、大脑激活和脑化学之间的关系；3)研究大脑异常和免疫功能之间的关系(通过免疫部分进行评估)。受试者将与免疫部分研究的受试者重叠。 项目I免疫学组成部分(Robert Fujinami博士，第96-130页) 描述[申请人提供]：免疫学项目建议调查5-羟色胺在诱导免疫反应失调中的作用。研究人员将检查自闭症儿童中存在的T细胞和抗体的特异性和自身反应性。他将确定免疫效应细胞和抗体是否诱导或模仿自闭症患者经常观察到的中枢神经系统特征，如海马体和乳头体的变化。最后，他建议对自闭症儿童和对照受试者外周血单核细胞中分离出的RNA进行微阵列分析。

DESCRIPTION (provided by the applicant): This renewal application proposes three projects and three cores to extend studies of phenotypes associated with autism. The Immune Component will address four specific aims: 1) investigate the interaction between serotonin and immune dysregulation; 2) characterize the specificity and autoreactivity of T cells and antibodies in subjects with autism; The Genetics Component will collect DNA and clinical information on affected cases and relatives (including intermediate phenotypes, broader autism phenotype, head circumference, serotonin levels, and stored serum for immune phenotypes identified by the Immune Component). Assessments will be done on five extended Utah kindreds already identified through the Utah Population Data Base, and on two new extended pedigrees to be identified through a new UPDB search of 800 new autism cases identified through surveys and the State Health Department and University of Utah Clinics. A 5 cM genome scan will be done using the Marshfield Mammalian Genotyping Service. Pedigrees will be analyzed using the clinical phenotype and intermediate phenotypes to map susceptibility loci. Five candidate genes under linkage peaks and/or identified by the Immune Component will be genotyped using SNPs. DNA, whole blood (for future serotonin), and serum (for future immune phenotyping) will be stored on the 800 new autism cases and their parents for future family-based association studies. The Neuroimaging Component will study persons with autism, employing structural and functional imaging studies to address the following specific aims: 1) describe longitudinal changes in structural brain volumes and their relationships to changes in clinical phenotypes; 2) describe relationships among brain structure, white matter structure and integrity, brain activation, and brain chemistry; 3) study associations between abnormalities of the brain and immune function (as assessed by the Immune Component). Subjects will overlap with those studied by the Immune Component. COMPONENT PROJECTSPROJECT I Immunology (Robert Fujinami, Ph.D., pp. 96-130) DESCRIPTION [provided by applicant]: The Immunology Project proposes to investigate the role of serotonin in inducing dysregulation of the immune response. The investigator will examine the specificity and autoreactivity of T cells and antibodies present in children with autism. He will determine whether immune effector cells and antibodies induce or mimic CNS features often observed in autistic subjects such as hippocampal and mammillary body changes. Finally, he proposes to perform microarray analyses on RNA isolated from peripheral blood mononucler cells of autistic children versus control subjects.