A New Animal Model to Examine Nervous System Function Development and Regeneration

一种检查神经系统功能发育和再生的新动物模型

基本信息

批准号：
10703706
负责人：
Brandon Weissbourd
金额：
$ 24.9万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-15 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10703706
关键词：
Ablation Action Potentials Animal Behavior Animal Model Animals Axon Bacteria Behavior Behavioral Biological Biological Models Biological Process Biology Body part Cells Clustered Regularly Interspaced Short Palindromic Repeats Communities Complex Cues DNA Data Development Developmental Process Disease Food Foundations Future Gene Transfer Techniques Genetic Genetic Models Genetic Techniques Goals Grant Health Human Image Injury Investigation Jellyfish Knock-in Knock-out Knowledge Link Longevity Maps Measures Modeling Modernization Molecular Natural regeneration Nerve Regeneration Nervous System Nervous System Physiology Neurons Neuropeptides Neurosciences Nuclear Import Numeric Rating Scale Optics Oral cavity Organism Peptides Pharmaceutical Preparations Physiology Population Positioning Attribute Postdoctoral Fellow Property Publishing RFamide peptide Reagent Recovery Research Resolution Role Science Sodium Structure System Techniques Testing Traction Training Transgenic Organisms Vision Whole Organism Work analytical tool arginylphenylalaninamide biomarker identification calcium indicator cell motility cell type coping healing in vivo innovation insight migration millisecond model organism molecular phenotype neural neurodevelopment neurogenesis neuromechanism neuroregulation newborn neuron novel optogenetics programs regeneration following injury regenerative single-cell RNA sequencing theories

项目摘要

Model organisms have proven invaluable as more tractable systems to study fundamental principles of biology and by yielding breakthroughs that result from studying evolutionary innovations, for example, GFP, from jellyfish, or CRISPR, from bacteria. My goal is to leverage a new model system, developed during my postdoctoral work, that is uniquely positioned to provide insights of both types: Clytia hemisphaerica, a species of Mediterranean jellyfish. This proposal uses Clytia's distinctive features to identify precise mechanisms at the interface of neural development, neural regeneration, and systems neuroscience. First, Clytia are tiny (<1mm-1cm), transparent, and genetically tractable, making it possible to image and manipulate the activity of every neuron in the nervous system simultaneously, in vivo, using genetically encoded optical techniques. Further, Clytia numerically scale their nervous system at least an order of magnitude during their lifespan without disrupting system function, ending with more than ten thousand neurons. It is therefore also possible to observe continuous differentiation, migration, axon targeting, and functional activity simultaneously across the whole organism. Lastly, Clytia have poorly understood and powerful regenerative capabilities. These include the regeneration of large populations of genetically ablated neurons, with rapid recovery of the behaviors that those neurons control. These properties make Clytia an experimentally tractable platform to investigate: · Fundamental questions in systems neuroscience, including mechanisms underlying behaviors and behavior states, roles of neuromodulation, and approaches for studying system organization and function across scales. · Basic principles of neurodevelopment, particularly at the interface of development and function. · Mechanisms enabling regeneration and the seamless integration of new neurons into a functioning network. In Aim 1, I will characterize the molecular phenotypes of neurons and establish CRISPR-based knock-in to target effectors to specific subpopulations of cells. In Aim 2, I will use a coordinated behavior as my point of entry and develop and test models of underlying neural mechanisms. In Aim 3, I will examine how this behavioral system is robust to constant neurogenesis, and the mechanisms that enable its rapid recovery following genetic ablation of neurons. My vision is that, once the key foundational work has been completed and published, Clytia will become a widely used model system. This proposal serves as the first step, laying the foundation for my future independent program and for a Clytia community more broadly, and providing the essential training that I need to fill gaps in my knowledge, focusing on computational and single-cell RNA sequencing approaches.

模型生物已被证明是非常有价值的，作为更易于处理的系统来研究生物学的基本原理，并通过研究进化创新（例如来自水母的 GFP 或来自细菌的 CRISPR）而取得突破，我的目标是利用新的模型系统，在我的博士后工作期间开发的，它具有独特的定位，可以提供两种类型的见解：Clytia hemisphaerica，地中海水母的一种。该提案利用 Clytia 的独特特征来识别界面的精确机制。首先，Clytia 很小（<1mm-1cm）、透明且易于遗传，使得在体内同时成像和操纵神经系统中每个神经元的活动成为可能。此外，Clytia 在其生命周期中将其神经系统的数量级扩展至少一个数量级，而不会破坏系统功能，最终有超过一万个神经元，因此也可以观察到连续的分化、迁移、最后，Clytia 具有我们知之甚少的强大再生能力，其中包括大量基因消融的神经元的再生，以及这些神经元控制的行为的快速恢复。一个实验上易于处理的平台，用于研究： · 系统神经科学的基本问题，包括行为和行为状态的机制、神经调节的作用以及跨尺度研究系统组织和功能的方法 · 神经发育的基本原理，特别是在神经发育方面。 · 实现新神经元再生和无缝整合到功能网络中的机制。在目标 1 中，我将表征神经元的分子表型，并建立基于 CRISPR 的基因敲入，以将效应子靶向特定的细胞亚群。在目标 2 中，我将使用协调行为作为切入点，并开发和测试潜在神经机制的模型。在目标 3 中，我将研究这种行为系统如何对持续的神经发生具有鲁棒性，以及实现其快速发生的机制。我的愿景是，一旦关键的基础工作完成并发表，Clytia 将成为一个广泛使用的模型系统，这一提议作为第一步，为我未来的独立项目和项目奠定基础。更广泛的 Clytia 社区，并提供我需要的基本培训来填补我的知识空白，重点是计算和单细胞 RNA 测序方法。