Gene Regulatory Networks of Synaptic Specificity

突触特异性的基因调控网络

基本信息

批准号：
10351552
负责人：
Mehmet Neset Ozel
金额：
$ 12.69万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10351552
关键词：
ATAC-seq Address Adult Affect Algorithms Award Biological Models Blindness Blood Coagulation Factor VII Brain Brain Injuries Brain region Calcium Candidate Disease Gene Cell Surface Proteins Cells Chromatin Code Collaborations Complex Computational Technique Computer Models Data Data Set Defect Detection Development Developmental Gene Drosophila genus Electrophysiology (science)Engineering Environment Equilibrium Gene Expression Regulation Genes Genetic Genetic Transcription Genetic study Genomics Goals Human Image Individual Knowledge Lead Learning Link Logic Mediating Mentors Mentorship Methods Modeling Modification Molecular Morphology Motion Nerve Degeneration Nervous system structure Neurodevelopmental Disorder Neurons Neurophysiology - biologic function New York Optic Lobe Output Phase Physiological Physiology Process Property RNA Regenerative Medicine Regulator Genes Research Resources Retina Specificity Synapses System Techniques Testing Time Training Transplantation Universities Visual Visual system structure Work XCL1 gene base cell replacement therapy cell type effective therapy experimental study fly gene regulatory network improved in vivo in vivo calcium imaging induced pluripotent stem cell interest machine learning framework nerve stem cell network models neural circuit neuron development neuroregulation novel strategies postsynaptic programs relating to nervous system response single-cell RNA sequencing stem cells synaptogenesis tool transcription factor transcriptome transdifferentiation

ATAC-seq Address Adult Affect Algorithms Award Biological Models Blindness Blood Coagulation Factor VII Brain Brain Injuries Brain region Calcium Candidate Disease Gene Cell Surface Proteins Cells Chromatin Code Collaborations Complex Computational Technique Computer Models Data Data Set Defect Detection Development Developmental Gene Drosophila genus Electrophysiology (science)Engineering Environment Equilibrium Gene Expression Regulation Genes Genetic Genetic Transcription Genetic study Genomics Goals Human Image Individual Knowledge Lead Learning Link Logic Mediating Mentors Mentorship Methods Modeling Modification Molecular Morphology Motion Nerve Degeneration Nervous system structure Neurodevelopmental Disorder Neurons Neurophysiology - biologic function New York Optic Lobe Output Phase Physiological Physiology Process Property RNA Regenerative Medicine Regulator Genes Research Resources Retina Specificity Synapses System Techniques Testing Time Training Transplantation Universities Visual Visual system structure Work XCL1 gene base cell replacement therapy cell type effective therapy experimental study fly gene regulatory network improved in vivo in vivo calcium imaging induced pluripotent stem cell interest machine learning framework nerve stem cell network models neural circuit neuron development neuroregulation novel strategies postsynaptic programs relating to nervous system response single-cell RNA sequencing stem cells synaptogenesis tool transcription factor transcriptome transdifferentiation

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项目摘要

Project Summary/Abstract Neuronal type identity is central to the development and function of neural circuits, as it instructs both the connectivity of neurons as well as their synaptic and electrophysiological properties. Neuronal fates are thought to be controlled by combinations of transcription factors (TF) known as terminal selectors, but very little is known about the gene regulatory mechanisms that link differential TF expression to specific neuronal features. The Drosophila visual system, a well-characterized brain region that has an organization analogous to the vertebrate retina and cortex, provides the ideal balance of complexity and accessibility to investigate these mechanisms. The first aim of this project will be to decipher the terminal selector TF codes that establish and maintain the unique identity of approximately 200 neuronal types that make the Drosophila optic lobes. Using a single-cell RNA sequencing (scRNA-seq) dataset I generated from developing optic lobes, I identified the combinations of TFs that are stably maintained in each neuronal type throughout their differentiation. Under the mentorship of Claude Desplan (K99 phase), I will test the hypothesis that these TFs function as terminal selectors by modifying the TF codes of specific optic lobe neurons in vivo, with the goal of predictably transdifferentiating them into other cell types. This will demonstrate the sufficiency of terminal selectors to confer neuronal identity and benefit the field of regenerative medicine. The conserved mechanisms in mammalian systems could be exploited to induce differentiation of pluripotent cells into specific neurons that could be transplanted to treat blindness or neurodegeneration. The second aim of this project will link the terminal selector TFs to their downstream targets. In collaboration with Richard Bonneau, I will learn to use the “Inferelator” algorithm to generate computational models of gene regulatory networks by combining my existing scRNA-seq data with new chromatin accessibility (scATAC-seq) data I will acquire. During the K99 phase, I will test the effects of perturbating key predicted downstream effectors on the morphology and connectivity of a select group of neurons to establish proof-of- concept. I will then generalize this approach in the R00 phase by inferring gene regulatory networks for all optic lobe neurons at multiple developmental stages. The third aim will be performed in my independent lab (R00) to utilize the network models for engineering precise modifications in visual circuits. I will seek to selectively uncouple the circuit that computes wide-field motion from the one that detects small moving objects. I will use synaptic tracing methods as well as intravital calcium imaging to demonstrate the functional consequences of developmental perturbations. Altogether, this project will establish direct mechanistic links between the encoding of neuronal identity and the molecules that mediate intercellular interactions during synaptic partner selection, which are commonly affected in neurodevelopmental disorders. The mentorship I will receive from Dr. Desplan and Dr. Bonneau, combined with the impressive resources of New York University provide the ideal environment for preparing me to build a successful independent research program that link gene regulation to brain wiring.

项目摘要/摘要神经元类型的身份对于神经回路的发展和功能至关重要，因为神经元的连通性及其突触和电生理特性。神经元的命运被认为由称为终端选择器的转录因子（TF）的组合控制，但鲜为人知关于将差异TF表达与特定神经元特征联系起来的基因调节机制。这果蝇视觉系统，一个特征良好的大脑区域，具有类似于脊椎动物的组织视网膜和皮层提供了研究这些机制的复杂性和可及性的理想平衡。该项目的第一个目的是破译终端选择器TF代码，以建立和维护大约200个神经元类型的独特身份，使果蝇视为爱。使用单细胞我从开发光学爱产生的RNA测序（SCRNA-SEQ）数据集，我确定了组合在每种神经元类型中均能稳定地保持其整个分化的TF。在 Claude Desplan（K99阶段），我将通过修改来测试这些TFs作为终端选择器的假设体内特定光叶神经元的TF代码，目的是将其转变为其他细胞类型。这将证明终端选择器具有赋予神经元身份并受益再生医学领域。可以利用哺乳动物系统中的配置机制来诱导多能细胞分化为特定神经元，这些神经元可以移植以治疗失明或神经变性。该项目的第二个目标将将终端选择器TFS与其下游目标联系起来。与理查德·邦诺（Richard Bonneau）合作，我将学习使用“地狱者”算法来生成计算通过将我现有的SCRNA-SEQ数据与新的染色质可访问性相结合，基因调节网络的模型（scatac-seq）我将获得的数据。在K99阶段，我将测试扰动密钥预测的效果下游对精选神经元的形态和连通性的影响，以建立证明证明概念。然后，我将通过推断所有Optic的基因调节网络来概括R00阶段的方法在多个发育阶段的叶神经元。第三个目标将在我的独立实验室（R00）中进行利用网络模型进行视觉电路中的工程精度修改。我将寻求选择性地从检测到小移动物体的电路中取消计算宽视野运动的电路。我会用突触跟踪方法以及浸润钙成像，以证明发育扰动。总之，该项目将在编码之间建立直接的机械链接神经元认同和突触伴侣选择过程中培养基间相互作用的分子，通常在神经发育障碍中受到影响。我将从Desplan博士那里收到的精神职位 Bonneau博士加上纽约大学的令人印象深刻的资源提供了理想的环境为了使我准备建立成功的独立研究计划，该计划将基因调节与大脑接线联系起来。