Genetic Influences on Human Cortical Development

描述(申请人提供)：精神分裂症和自闭症等神经精神疾病会给个人带来衰弱的后果，并导致护理成本飙升，给患者和社会带来巨大负担。目前的治疗状况仍然受到不良结果的困扰。基因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。人类神经前体细胞可以用来在培养皿中模拟皮质发育的各个方面，从而允许高通量地研究与疾病相关的表型。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，(2)神经元形态和突触发生。利用从大约150个供体系神经前体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数量方面的特定遗传变异。这将构成对影响人类细胞神经发育表型的遗传位点的第一次系统鉴定。我们将利用大脑皮层发育的模型系统，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。一旦确定了神经发育数量性状基因座，我们将利用最近可用的基因组工程技术来寻找遗传变异导致表型变化的机制。利用生物信息学和分子克隆，我们将在人类神经前体细胞的基因组中引入对皮质发育具有已证实影响的突变。疾病相关过程的特定细胞模型将为治疗药物的发现、开发和快速筛选打开大门。为了完成拟议的研究计划，我将在导师的监督和指导下，在神经发育生物学、遗传学和生物信息学方面进行为期两年的强化培训。丹尼尔·格施温德，医学博士，我的主要导师，神经发育生物学和遗传学方面的专家，以及Eleazar Ekin，博士，我的共同导师，生物信息学和统计遗传学的专家，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、高内容筛选和计算集群资源，我将能够利用最新的技术高效地完成这些研究。凭借从这个项目中学到的技能，我将过渡到学术教职，成为一名独立的调查员，从事神经精神障碍的转化性研究。

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.