Mapping Regulatory Networks of Autism Risk at Cellular Resolution during Neurodevelopment

绘制神经发育过程中细胞分辨率的自闭症风险监管网络

基本信息

批准号：
10006848
负责人：
Rebecca Ann Muhle
金额：
$ 15.41万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-18 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10006848
关键词：
Address Adult Affect Affinity Animal Model Behavioral Symptoms Binding Biological Biological Assay Biological Availability Biological Models Biological Response Modifier Therapy Biology Biotin Brain Cell model Cells Child Child Psychiatry Collaborations Congenital Disorders Cre driver DNA-Binding Proteins Data Development Disease Doctor of Medicine Doctor of Philosophy Education Embryo Employment Engineering Etiology Evolution Exposure to Expression Profiling Foundations Future Gene Expression Genes Genetic Genetic Diseases Genetic Heterogeneity Genetic study Genomics Goals Human Image Impairment Individual Investigation K-Series Research Career Programs Knockout Mice Knowledge Life Ligands Ligase Machine Learning Maps Mentorship Modeling Molecular Molecular Genetics Mus Mutation Neurodevelopmental Disorder Neurologic Neurons Pathology Pathway Analysis Pathway interactions Proteins Psychiatrist Public Health RNA Reporter Reporting Research Research Personnel Research Training Resolution Resources Risk Risk Factors Role Signal Pathway Site Statistical Models Symptoms Systems Analysis Systems Biology Time Tissues Training Programs Variant autism spectrum disorder base biochip career career development cell type chromatin immunoprecipitation chromatin remodeling differential expression disorder risk fetal functional genomics genetic architecture genetic risk factor genome-wide helicase innovation insight learning network mathematical model neocortical nerve stem cell neurobehavioral disorder neurodevelopment novel novel therapeutics risk variant single-cell RNA sequencing skills small molecule social communication targeted treatment therapeutic development therapeutic target tool transcriptome transcriptome sequencing transcriptomics

项目摘要

Project Summary Dr. Muhle is a practicing child psychiatrist with a strong track record of developing molecular and genetic tools to elucidate the mechanism of disease. The long-term goal of this career development award is to identify regulatory networks underlying autism spectrum disorder (ASD) through the integration of state-of-the- art functional genomics, single cell transcriptomics, and systems biology analyses with precision-engineered models of early brain development. She initiated this project during her time in the Adult and Child Psychiatry Research Training Program at the Yale Child Study Center, with the mentorship of James Noonan, Ph.D. and co-mentorship of Matthew State, M.D., Ph.D. With the guidance of Dr. Noonan, a world-wide leader in using functional genomics to understand development and evolution, and the support of Dr. State, an undisputed pioneer and leader in ASD genetics, Dr. Muhle developed expertise in regulatory genomics and the genetic architecture of ASD. Her career goal is to become an independent investigator, examining the role of the ASD risk gene Chromodomain Helicase DNA-binding Protein 8 (CHD8) in the development of ASD. Her research goal is to determine the role of CHD8 and the impact of its loss on regulatory networks. Our hypothesis is that CHD8 regulates ASD risk-associated networks in specific cell-types that become dysregulated when CHD8 expression is altered. To address these questions, she successfully generated a Chd8 constitutive knockout mouse and an Avi-tagged Chd8 mouse that she will use to identify Chd8-regulated networks in specific cell-types at high cellular resolution. She also proposes a high-throughput small molecule screen to explore potential upstream developmental signaling pathways that effect CHD8-regulated expression networks. The following independent specific aims will address our hypothesis: 1) Determine cell-type specific expression changes due to Chd8 haploinsufficiency in the developing cortex. 2) Map Chd8-bound cell-type specific regulatory networks at high resolution in the cortex. 3) Identify bioactive modulators of CHD8 expression networks via high-throughput reporter assay. Our rationale is that by studying CHD8, a key regulatory molecule that targets other ASD risk genes, we will expand our knowledge of other ASD risk genes and identify CHD8-targeted regulatory networks in particular cell-types to further define the biology of ASD. With the continued mentorship of Dr. Noonan and co-mentorship of Marina Picciotto, M.D., an expert in animal models of neurobehavioral disorders, with collaboration of Thomas Fernandez, M.D., a child psychiatrist with expertise in systems analyses of genetic risk factors, and Smita Krishnaswamy, Ph.D., a computational biologist on the cutting-edge of statistical and mathematical modeling, Dr. Muhle will develop the experimental and analytical skills necessary to fully utilize the model systems she has developed. Together with the resources of the Yale Child Study Center and her career development goals, she will attain her career goal to illuminate basic biological mechanisms underlying brain development and risk for ASD.

项目概要 Muhle 博士是一位执业儿童精神病学家，在发展分子和精神疾病方面拥有丰富的记录。阐明疾病机制的遗传工具。该职业发展奖的长期目标是通过整合最新的信息来识别自闭症谱系障碍（ASD）背后的监管网络精确设计的艺术功能基因组学、单细胞转录组学和系统生物学分析早期大脑发育模型。她在成人和儿童精神病学期间发起了这个项目耶鲁儿童研究中心的研究培训项目，由 James Noonan 博士指导。和 Matthew State 医学博士、哲学博士的共同导师在世界使用领域领导者 Noonan 博士的指导下功能基因组学来理解发育和进化，以及 State 博士的支持，无可争议 Muhle 博士是自闭症谱系障碍 (ASD) 遗传学领域的先驱和领导者，在调控基因组学和遗传学方面积累了丰富的专业知识。 ASD 的架构。她的职业目标是成为一名独立调查员，研究 ASD 的作用 ASD 发展中的风险基因 Chromodomain 解旋酶 DNA 结合蛋白 8 (CHD8)。她的研究目标是确定 CHD8 的作用及其丢失对监管网络的影响。我们的假设是，CHD8 调节特定细胞类型中与 ASD 风险相关的网络，这些网络成为当 CHD8 表达改变时，失调。为了解决这些问题，她成功地生成了一个 Chd8 组成型敲除小鼠和 Avi 标记的 Chd8 小鼠，她将用它来识别 Chd8 调节以高细胞分辨率在特定细胞类型中构建网络。她还提出了一种高通量小分子筛选以探索影响 CHD8 调节表达的潜在上游发育信号通路网络。以下独立的具体目标将解决我们的假设：1）确定细胞类型特异性由于发育中皮质中 Chd8 单倍体不足，表达发生变化。 2) 绘制 Chd8 结合细胞类型皮质中高分辨率的特定调节网络。 3) 鉴定CHD8的生物活性调节剂通过高通量报告基因检测表达网络。我们的理由是，通过研究 CHD8，针对其他 ASD 风险基因的调控分子，我们将扩大对其他 ASD 风险基因的了解并确定特定细胞类型中的 CHD8 靶向调控网络，以进一步定义 ASD 的生物学。在 Noonan 博士的持续指导和医学专家 Marina Picciotto 的共同指导下神经行为障碍的动物模型，与儿童 Thomas Fernandez 医学博士合作具有遗传风险因素系统分析专业知识的精神病学家，以及 Smita Krishnaswamy 博士、 Muhle 博士是统计和数学建模前沿的计算生物学家，他将开发充分利用她开发的模型系统所需的实验和分析技能。一起凭借耶鲁儿童研究中心的资源和她的职业发展目标，她将实现她的职业生涯目标是阐明大脑发育和自闭症谱系障碍风险的基本生物学机制。