Gene Expression and Immune Cell Function in Mothers of Children with Autism

描述（由申请人提供）：本提案是为了响应以下标题而提交的：恢复法案有限竞争：研究解决自闭症谱系障碍（R21）中的异质性。申请表（RFA）编号：RFA-MH-09-172摘要：虽然大多数研究都研究了自闭症儿童的免疫异常，但也有可能在母亲脆弱的神经发育的关键时期出现异常的免疫反应，可能会在胎儿或新生儿大脑中产生神经元损伤，并产生自闭症的长期神经功能障碍特征。我们将检查自闭症儿童母亲血液中免疫细胞的几个可量化的生物特征：（1）RNA水平，（2）白色血细胞的功能测定和（3）针对胎儿脑蛋白的抗体的存在。我们的初步数据显示，一些自闭症儿童的母亲在外周血中的RNA表达谱与对照儿童的母亲不同。我们发现，一些自闭症儿童血液中的自然杀伤（NK）细胞功能受损。我们还发现，一些自闭症儿童的母亲血液中有针对胎儿大脑蛋白的抗体。基于这些令人鼓舞的发现，我们为这一探索性的R21提出了以下具体目标。具体目标#1。确定是否有自闭症儿童的母亲在其外周血中具有不同的RNA表达谱的亚组，这些亚组彼此不同，并且与对照组不同。具体目标#2：检查自闭症儿童母亲的自然杀伤（NK）细胞功能; NK功能的变化是否与NK基因表达的变化有关;以及这些母亲中是否有NK细胞功能异常的自闭症儿童。具体目标#3确定自闭症儿童的母亲是否具有针对胎儿脑蛋白的抗体，并且在血液中可检测到，具有与其他自闭症儿童的母亲不同的异常NK功能和/或血液中异常的RNA表达谱，并且与正常发育儿童的母亲不同。假设条件：我们假设有一个自闭症儿童的母亲亚组，其外周血中可检测到免疫异常，可以通过以下方法进行评估：（1）免疫/白色血细胞中的RNA表达;（2）白色血细胞的功能测定;（3）显示血液中存在针对胎儿脑蛋白的抗体。 意义和影响。将自闭症儿童的母亲亚组鉴定为特定免疫相关表型的能力将提高连锁和全基因组关联研究的成功率，以检测与该亚组相关的基因。识别与自闭症儿童高度相关的母亲的生物特征，最终可能导致自闭症儿童母亲的特异性免疫异常的特征，并可能揭示该亚组中自闭症的原因，并可能导致怀孕前或怀孕期间的预防或治疗策略。 公共卫生相关性：自闭症儿童母亲的免疫系统相对较少受到关注。母亲的免疫系统很重要，因为怀孕期间免疫反应失调可能会影响胎儿的大脑，导致自闭症。因此，该提案将重点关注患有自闭症儿童的妇女的免疫系统，与典型发育儿童的妇女相比。

DESCRIPTION (provided by applicant): This proposal is submitted in response to the following Title: Recovery Act Limited Competition: Research to Address the Heterogeneity in Autism Spectrum Disorders (R21). Request for Applications (RFA) Number: RFA-MH-09-172 Abstract: Though most studies have examined immune abnormalities in children with autism, it is also possible that an aberrant immune response in mothers during vulnerable, critical periods of neurodevelopment could produce neuronal injury in the fetal or neonatal brain, and produce long term neurological dysfunction characteristic of autism. We will examine several quantifiable biological signatures of immune cells in blood of mothers of children with autism: (1) RNA levels, (2) functional assays of white blood cells and (3) the presence of antibodies that are directed to fetal-brain proteins. We have preliminary data showing that a number of mothers of children with autism have RNA expression profiles in their peripheral blood that differ from mothers of control children. We have discovered that the function of Natural Killer (NK) cells in blood of a number of children with autism is impaired. We have also discovered that some mothers of children with autism have antibodies in their blood that are directed at fetal-brain proteins. Based upon these promising findings, we propose the following Specific Aims for this exploratory R21. Specific Aim #1. Determine whether there are subgroups of mothers of children with autism with different RNA expression profiles in their peripheral blood that differ from each other and differ from controls. Specific Aim #2: Examine Natural Killer (NK) cell function in mothers of children with autism; whether the NK functional changes are associated with changes of NK gene expression; and whether some of these mothers have autistic children with abnormal NK cell function. Specific Aim #3. Determine whether mothers of children with autism, who have antibodies that are directed at fetal-brain proteins and which are detectable in blood, have abnormal NK function and/or abnormal RNA expression profiles in blood that differ from other mothers of children with autism and differ from mothers of typically developing children. Hypotheses: We postulate that there is a subgroup of mothers with children with autism who has an immune abnormality detectable in peripheral blood that can be assessed using (1) RNA expression in the immune/ white blood cells (2) functional assays of white blood cells and (3) and by showing the presence of antibodies directed to fetal-brain proteins in blood. Significance and Impact. The ability to identify a subgroup of mothers of children with autism into a specific immune-related phenotype will improve the success of linkage and whole genome association studies to detect genes associated with this subgroup. The identification of biological signatures in mothers that are highly associated with having children with autism could eventually lead to the characterization of specific immune abnormalities in the mothers of children with autism and may shed light on the cause(s) of autism in this subgroup and potentially lead to prevention or treatment strategies prior to or during pregnancy. PUBLIC HEALTH RELEVANCE: There has been relatively little attention paid to the immune system of mothers of children with autism. The maternal immune system is important since a dysfunctional immune response during pregnancy might affect the fetal brain and result in autism. Thus, this proposal will focus on the immune system of women with children with autism compared to women of typically developing children.