Revealing the transcriptional and developmental mechanisms of interneuron identity

揭示中间神经元身份的转录和发育机制

• 批准号: 9754408
• 负责人: MEGAN CROW
• 金额: $ 11.84万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9754408
• 关键词: Adult; Advisory Committees; BRAIN initiative; Binding; Biology; Brain; Caliber; Cell Communication; Cell Maintenance; Cell physiology; Cells; Chromatin; Code; Collaborations; Complex; Computing Methodologies; Data; Data Set; Development; Developmental Gene; Developmental Process; Disease; Educational workshop; Ensure; Environment; Epigenetic Process; Fire - disasters; Functional disorder; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Engineering; Genetic Transcription; Goals; Heterogeneity; Human; Individual; Institutes; International; Interneurons; Investigation; Lateral Geniculate Body; Lead; Light; Link; Machine Learning; Maintenance; Mentors; Mentorship; Meta-Analysis; Methods; Molecular; Multiomic Data; Mus; Neurobiology; Neurons; Pathogenesis; Phenotype; Phylogenetic Analysis; Play; Portraits; Positioning Attribute; Primates; Process; Regulator Genes; Research; Resolution; Role; Shapes; Techniques; Technology; Time; Training; Universities; Validation; base; career development; cell type; comparative genomics; data integration; design; developmental neurobiology; differential expression; epigenomics; experience; genomic data; improved; insight; learning strategy; member; methylome; neural circuit; neuroinformatics; novel; programs; relating to nervous system; single-cell RNA sequencing; skills training; student mentoring; symposium; tool; transcription factor; transcriptome; transcriptome sequencing

Cortical GABAergic interneurons are critical components of neural circuitry, and their dysfunction has been linked to neurodevelopmental diseases. Although the diversity of interneurons is not disputed, both the extent of their heterogeneity and the gene regulatory mechanisms that drive it remain unclear. Recent advances in single cell RNA-sequencing technology have shed new light on this issue, enabling the prediction of novel interneuron subtypes based on gene expression. Cross-species meta-analysis would provide key insight into conserved mechanisms of interneuron diversity. However, cross-study integration remains a major challenge. I hypothesize that interneuron identity is defined by unifying molecular processes across species. This project is designed to reveal these processes by using an integrative, cross-species approach to explore the transcriptional, epigenetic, and developmental mechanisms that govern interneuron diversity. First, I have shown that mouse interneuron subtypes replicably express genes associated with cell-cell communication, enabling cross-dataset meta-analysis. The goal of Aim 1 is to use improved computational and phylogenetic methods to define homologous interneuron subtypes across species and identify robust gene targets. Second, preliminary investigation of single cell methylome-sequencing data indicates that it can be readily aligned with expression data. In Aim 2 I will use machine learning methods to generate networks from epigenomic and expression data and identify subtype-specific regulatory features. Third, I have shown that transcriptional profiles from developing neurons can be quantitatively assessed with respect to adult expression data. Aim 3 will use meta-analytic aggregation of temporal inference methods to enable cross-dataset comparisons and define conserved developmental gene programs. These studies will reveal a multidimensional portrait of interneuron molecular identity and enable genetic access to these cell types, a key aim of the BRAIN Initiative. I also propose an extensive training plan that will support my transition to independence. CSHL provides an outstanding research environment, with unequaled opportunities for scientific discussion, advanced skills training and career development. I have assembled an exceptional team of collaborators and mentors who will help me to achieve my goals. Dr. Jesse Gillis, expert in transcriptome meta-analysis, and Dr. Josh Huang, expert in GABAergic interneuron identity, will be my mentors. Dr. Bing Ren, Dr. Adam Siepel, Dr. Guoping Feng, Dr. Jessica Tollkuhn and Dr. Michael Greenberg will be collaborators and members of my advisory committee, ensuring that my research will be of the highest caliber. My training will also involve coursework in multiomics data integration and comparative genomics, and I will continue my professional development by presenting at international conferences, mentoring students and attending workshops at CSHL. Together, the proposed studies and professional training will ensure my successful transition to an independent position at a major university where I will lead a lab that will advance the goals of the BRAIN Initiative.

皮质GABA能中间神经元是神经回路的关键组成部分，它们的功能障碍一直是 与神经发育疾病有关。尽管中间神经元的多样性没有争议，但两种程度 它们的异质性和驱动它的基因调节机制尚不清楚。最近的进步 单细胞RNA序列技术为这个问题提供了新的启示，以实现新颖的预测 基于基因表达的中神经元亚型。跨物种荟萃分析将为您提供关键的见解 中间神经多样性的保守机制。但是，跨研究仍然是一个重大挑战。 我假设中间神经元的身份是通过统一物种的分子过程来定义的。这个项目 旨在通过使用集成的跨物种方法来探索这些过程 控制间神经多样性的转录，表观遗传和发育机制。首先，我有 表明小鼠间神经元亚型可复制地表达与细胞 - 细胞通信相关的基因， 启用跨数据集荟萃分析。目标1的目的是使用改进的计算和系统发育 定义物种跨物种的同源间ron类亚型并确定稳健基因靶标的方法。第二， 对单细胞甲基甲基序列数据的初步研究表明，它可以很容易地与 表达数据。在AIM 2中，我将使用机器学习方法来从表观基因组生成网络和 表达数据并确定亚型特异性调节特征。第三，我已经证明了转录 可以针对成人表达数据进行定量评估发育中的神经元的谱。目标3 将使用时间推理方法的荟萃分析聚集来实现跨数据库的比较和 定义保守的发展基因程序。这些研究将揭示一张多维的肖像 内神经元的分子身份并使遗传获取这些细胞类型，这是大脑倡议的关键目的。 我还建议一项广泛的培训计划，以支持我向独立的过渡。 CSHL提供 杰出的研究环境，有无与伦比的科学讨论机会，高级技能 培训和职业发展。我组建了一个杰出的合作者和导师团队 帮助我实现自己的目标。转录组荟萃分析专家Jesse Gillis博士和Josh Huang博士 Gabaergic Interneuron身份的专家将成为我的导师。 Bing Ren博士，Adam Siepel博士，Guoping博士 Feng，Jessica Tollkuhn博士和Michael Greenberg博士将成为我的咨询公司的合作者和成员 委员会，确保我的研究将是最高的。我的培训也将涉及课程 多组合数据集成和比较基因组学，我将继续我的专业发展 在国际会议上演讲，指导学生并参加CSHL的讲习班。在一起， 拟议的研究和专业培训将确保我成功地过渡到一个独立的职位 我将领导一个实验室的大型大学，该实验室将促进大脑倡议的目标。