Genetic Influences on Human Cortical Development

描述（由申请人提供）：精神分裂症和自闭症等神经精神疾病对个人造成了衰弱的后果，护理费用飙升，给患者和社会造成了巨大的负担。目前的治疗状况仍然受到疗效不佳的困扰。遗传介导的大脑皮层发育和结构异常在这些疾病中起着重要作用。人类神经祖细胞可用于模拟培养皿中皮质发育的各个方面，从而允许对疾病相关表型进行高通量研究。在这里，我们将研究人类皮质发育的两个关键特征的遗传基础：（1）基因表达的纵向变化，以及（2）神经元形态和突触发生。利用在大约150个供体系的神经祖细胞中观察到的固有遗传变异，我们将进行纵向全基因组关联研究，以确定控制人类皮质发育定量方面的特定遗传变异。这将构成第一个系统的识别影响人类细胞神经发育表型的遗传位点。我们将使用皮质发育的模型系统来弥合遗传变异、分子和细胞生物学以及疾病状态之间的差距。一旦神经发育的数量性状位点被确定，我们将寻找一种机制，遗传变异导致表型变化，使用最近可用的基因组工程技术。利用生物信息学和分子克隆技术，我们将在人类神经前体细胞的基因组中引入对皮质发育有明显影响的突变。疾病相关过程的细胞特异性模型将为发现、开发和快速筛选治疗药物打开大门。为了完成这项研究计划，我将在导师的指导和监督下，接受为期两年的神经发育生物学、遗传学和生物信息学方面的强化培训。丹尼尔Geschwind，医学博士，博士，我的主要导师和神经发育生物学和遗传学专家，沿着Eliazar Eskin，博士，我的共同导师和生物信息学和统计遗传学专家，将指导我成功完成这个项目所需的技能。利用加州大学洛杉矶分校的高通量测序、高含量筛选和计算集群资源，我将能够利用最新的技术有效地完成这些研究。从这个项目中学到的技能，我将过渡到学术教师作为一个独立的研究者，追求在神经精神疾病的转化研究。

DESCRIPTION (provided by applicant): Neuropsychiatric diseases like schizophrenia and autism have debilitating consequences to individuals and skyrocketing costs of care, creating a great burden to patients and society. The current state of treatment remains plagued by poor outcomes. Genetically mediated abnormalities in the development and architecture of the cerebral cortex play an important role in these diseases. Human neural progenitor cells can be used to model aspects of cortical development in a dish, permitting high-throughput study of disease-associated phenotypes. Here, we will study the genetic underpinnings of two key features of human cortical development: (1) longitudinal changes in gene expression, and (2) neuronal morphology and synaptogenesis. Utilizing the inherent genetic variation observed in neural progenitors from approximately 150 donor lines, we will conduct longitudinal genome-wide association studies to identify the specific genetic variants governing quantitative aspects of human cortical development. This will constitute the first systematic identification of genetic loci influencing cellular neurodevelopmental phenotypes in human cells. We will bridge the gap between genetic variants, molecular and cellular biology, and disease states using model systems of cortical development. Once neurodevelopmental quantitative trait loci are identified, we will then search for a mechanism by which genetic variation causes phenotypic change using recently available genomic engineering techniques. Employing bioinformatics and molecular cloning, we will introduce mutations which have a demonstrated effect on cortical development into the genome of human neural progenitor cells. Cell specific models of disease- related processes will open the door for the discovery, development, and rapid screening of therapeutics. To accomplish the proposed research plan, I will pursue two years of intensive training in neurodevelopmental biology, genetics, and bioinformatics under the supervision and guidance of my mentors. Daniel Geschwind, MD, PhD, my primary mentor and an expert in neurodevelopmental biology and genetics, along with Eleazar Eskin, PhD, my co-mentor and an expert in bioinformatics and statistical genetics, will instruct me in the skills necessary to successfully complete this project. Using the high-throughput sequencing, high content screening, and computational cluster resources found at UCLA, I will be able to efficiently complete these studies with the most current technology available. With the skills learned from this project, I will transition to academic faculty as an independent investigator, pursuing translational research in neuropsychiatric disorders.