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Brain Abnormalities and Neurobehavioral Deficits in Hypoplastic Left Heart Syndrome

左心发育不全综合征的大脑异常和神经行为缺陷

基本信息

批准号：
10189677
负责人：
George Christopher Gabriel
金额：
$ 5.1万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-17 至 2024-05-16
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10189677
关键词：
Adult Affect Alleles Animal Model Aorta Architecture Automobile Driving Behavior Behavior assessment Behavioral Brain Cardiac Cardiac Surgery procedures Cell-Cell Adhesion Cerebral cortex Chromatin Chromatin Remodeling Factor Clinical Clinical Research Cognitive Complex Compulsive Behavior Congenital Heart Defects Corpus Callosum Cre driver Defect Development Developmental Delay Disorders Diffusion Magnetic Resonance Imaging Disease Dysplasia Etiology Exhibits Forebrain Development Future Genes Genetic Genetic Predisposition to Disease Heart Heart Abnormalities Heart Diseases Heart Transplantation Hippocampus (Brain)Histone Deacetylase Human Hypoplastic Left Heart Syndrome Infant Intervention Intrinsic factor Lead Learning Learning Disabilities Left Left ventricular structure Lesion LoxP-flanked allele Magnetic Resonance Imaging Mediating Memory Mentors Methyl-CpG-Binding Protein 2 Mitral Valve Molecular Molecular Profiling Morphology Motor Motor Skills Mus Mutagenesis Mutant Strains Mice Mutation Neurocognitive Deficit Neurodevelopmental Disability Neurodevelopmental Disorder Neurodevelopmental Impairment Operative Surgical Procedures Outcome Patient-Focused Outcomes Patients Perfusion Phenotype Population Prosencephalon Proteins Recovery Repression Repressor Proteins Rett Syndrome Risk Rodent Role Secondary to Side Structure Survivors Syndrome Testing Work autism spectrum disorder brain abnormalities clinically relevant congenital heart disorder de novo mutation design disease-causing mutation experience experimental study gene repression health related quality of life high risk improved improved outcome insight language impairment motor deficit mouse model multimodality mutant mouse model nervous system disorder neural network neurobehavioral neurobehavioral test neurodevelopment neurogenesis novel novel therapeutic intervention novel therapeutics olfactory bulb palliative prenatal prevent relating to nervous system social social deficits transcriptome transcriptome sequencing treatment strategy white matter

项目摘要

PROJECT SUMMARY Hypoplastic left heart syndrome (HLHS), a severe congenital heart disease (CHD), is associated with high risk for neurodevelopmental disabilities. In fact, over 30% of HLHS survivors experience moderate to severe neurocognitive impairment. While brain abnormalities in HLHS patients are typically thought to be secondary to substrate delivery deficits from circulatory disturbance, our recent recovery of HLHS mutant mice with brain abnormalities point to a shared genetic etiology for the heart defects and the neurodevelopmental disabilities. This is supported by other studies showing CHD patients with de novo mutations in chromatin modifying genes are at increased risk for neurodevelopmental disorders that can include cognitive, motor, social and language impairments. We observed HLHS mutant mice to have brain abnormalities involving the cortex, hippocampus, and olfactory bulb, forebrain structures also frequently affected in HLHS patients. We showed HLHS and brain abnormalities in the Ohia mouse line have a digenic etiology, arising from mutations in two genes: Sin3a- associated protein 130 (Sap130), a chromatin modifying protein mediating transcriptional repression, and protocadherin a9 (Pcdha9), a protein involved in cell-cell adhesion. As chromatin modifying genes are already implicated in autism and also in neurodevelopmental impairment in CHD patients, insights into the role of Sap130 in the brain defects of the Ohia HLHS mice will have broad relevance for understanding the causes for poor neurodevelopmental outcomes in CHD and non-CHD patients. In this study, we will investigate the hypothesis that Sap130 deficiency perturbs brain development, causing brain dysmaturation with altered neural network connectivity and neurobehavioral deficits. In Aim 1, we will investigate the cellular and molecular mechanisms driving the brain dysmaturation, focusing on the forebrain. This will entail examining neurogenesis and cortical plate formation and conducting molecular profiling with RNAseq and ChIPseq analyses. In Aim 2, we will conduct multi-modal structural magnetic resonance imaging (MRI) that will include diffusion tensor imaging (DTI) to characterize the forebrain dysplasia and neural network connectivity changes contributing to the brain dysmaturation defects. To determine if behavioral defects may be elicited by the brain dysmaturation and neural network connectivity perturbations, in Aim 3 we will conduct a battery of rodent neurobehavioral assessments. The studies in Aims 2 and 3 will be carried out using a floxed Sap130 allele with forebrain targeted Cre mediated Sap130 deletion. This will allow mutant mice to survive to adulthood without heart defects. Such mice will be generated with or without the Pcdha9 mutation, allowing determination of the role of Pcdha9 in the brain abnormalities. Together these studies will yield new insights into the developmental etiology of the HLHS associated brain abnormalities and whether specific changes in neural architecture may drive the associated neurobehavioral/neurocognitive impairments. These findings may form the basis for future development of novel therapeutics that can substantively improve outcome for this vulnerable CHD population.

项目总结左心发育不全综合征(HLHS)是一种严重的先天性心脏病，与高风险相关神经发育障碍患者。事实上，超过30%的HLHS幸存者经历了中度到重度神经认知障碍。而HLHS患者的脑异常通常被认为是继发性的循环障碍导致的底物递送缺陷，我们最近恢复了HLHS突变小鼠的脑异常指向心脏缺陷和神经发育障碍的共同遗传病因。这一点得到了其他研究的支持，这些研究表明冠心病患者染色质修饰基因发生了从头开始的突变患神经发育障碍的风险增加，包括认知、运动、社交和语言障碍减损。我们观察到HLHS突变小鼠有大脑异常，涉及皮质，海马体，而嗅球、前脑结构在HLHS患者中也经常受到影响。我们展示了HLHS和Brain 奥希亚小鼠品系的异常有病因，由两个基因突变引起：Sin3a- 相关蛋白130(Sap130)，一种介导转录抑制的染色质修饰蛋白，以及原钙粘附素A9(Pcdha9)，一种参与细胞间黏附的蛋白质。因为染色质修饰基因已经与自闭症和冠心病患者的神经发育障碍有关，对Sap130作用的洞察在OhiaHLHS小鼠的脑缺陷中，将有广泛的相关性来理解贫穷的原因冠心病和非冠心病患者的神经发育结局。在这项研究中，我们将调查这一假说 Sap130缺乏扰乱大脑发育，通过改变神经网络导致大脑不成熟连通性和神经行为缺陷。在目标1中，我们将研究细胞和分子机制。导致大脑发育不成熟，主要集中在前脑。这将需要检查神经发生和皮质平板形成和进行RNAseq和ChIPseq分析的分子图谱。在目标2中，我们将进行多模式结构磁共振成像(MRI)将包括扩散张量成像(DTI)以描述前脑发育不良和神经网络连通性改变对大脑的影响发育不成熟缺陷。以确定行为缺陷是否可能由大脑发育不成熟和神经引起在目标3中，我们将进行一系列啮齿动物神经行为评估。 AIMS 2和AIMS 3中的研究将使用前脑靶向Cre介导的FLOXED Sap130等位基因进行 Sap130缺失。这将使突变小鼠能够存活到成年，而不会出现心脏缺陷。这样的老鼠将会是产生或不产生Pcdha9突变，从而确定Pcdha9在大脑中的作用异常现象。总之，这些研究将为HLHS的发育病因提供新的见解相关的脑异常以及神经结构的特定变化是否可能推动相关的神经行为/神经认知障碍。这些发现可能会为小说未来的发展奠定基础能够实质性改善这一易受伤害的冠心病人群的预后的治疗方法。