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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：
10008391
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 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10008391
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 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.

项目总结