Cellular and Tissue Pathogenesis

细胞和组织发病机制

基本信息

批准号：
10221027
负责人：
Roy Vincent Sillitoe
金额：
$ 21.49万
依托单位：
BAYLOR COLLEGE OF MEDICINE
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：
2020-07-22 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10221027
关键词：
3-Dimensional Address Adult Affect Anatomy Animals Architecture Ataxia Behavior Behavioral Biological Models Birth Brain Cell model Cells Cellular Structures Child Child Health Cognitive Defect Development Diagnosis Disease Disease Outcome Disease model Drosophila genus Electrons Environmental Risk Factor Epilepsy Equipment Faculty Generations Genetic Genetic study Goals Histology Human Imaging technology Individual Induced pluripotent stem cell derived neurons Infrastructure Intellectual and Developmental Disabilities Research Centers Intellectual functioning disability Knowledge Lead Link Medicine Microscope Microscopy Modeling Modernization Molecular Motivation Motor Mus Nerve Degeneration Neuroglia Neurons Organ Organoids Pathogenesis Pathogenicity Pathologic Pathology Patients Personal Satisfaction Phenotype Population Positioning Attribute Postdoctoral Fellow Rattus Research Personnel Research Project Grants Resolution Resources Science Services Structure Synapses Techniques Tissues Training Transmission Electron Microscopy Work behavioral outcome brain abnormalities brain tissue cell type clinical phenotype cognitive function college confocal imaging design developmental disease effective therapy experience experimental analysis genome editing grasp human disease human model human tissue imaging capabilities imaging modality improved in utero in vitro Assay in vivo Model induced pluripotent stem cell innovation mouse genetics neural circuit neural correlate neuropathology response student training synergism tool transmission process two photon microscopy two-photon

项目摘要

Intellectual and developmental disabilities (IDDs) are common and have a devastating impact on child health around the world. Unfortunately, there are no effective treatments for the vast majority of IDDs and our understanding of the pathogenic mechanism for majority of IDDs is incomplete. A major impediment to solving how to better treat IDDs is our limited knowledge of how cells and tissues are impacted in each IDD. As a direct response to this problem, we have assembled the Cell and Tissue Pathogenesis Core (CTP Core) to study how brain anatomy and its associated pathologies arise. Our guiding rationale is that, solving how brain structure is wired in typical development will place us in an ideal position to uncover how faulty brain circuits eventually disrupt the ability to perform different behaviors in IDDs. Indeed, the pathological consequences of altering brain development typically present as severe motor or cognitive difficulties in children. The goal of the CTP Core is to provide our IDDRC Investigators with a centralized resource for comprehensive pathological examination of tissue, high-resolution two-photon and confocal imaging, ultra-structure tracking by electron microcopy, and the generation and characterization of human disease cellular models that are relevant to IDDs. By combining human cellular models, such as iPSC-derived neurons or glia, with deep structural and functional phenotyping of how the brain is mis-wired in different diseases or disease models, the CTP Core will provide a unique opportunity to address how distinct genetic and environmental factors may impact the brain and lead to alterations in cellular structure, connectivity and function. To accomplish these goals, we have divided the CTP Core into three sub-Cores that operate in parallel, but with the common goal of resolving brain structure as it relates to function and disease. The Neuropathology Sub-Core provides expertise in neuronal tissue analysis from basic histology and transmission electron microscopy to in-depth circuit analysis; the Microscopy Sub-Core provides access and training to state-of-the-art confocal and two-photon microscopy; and the Human Disease Cellular Models Sub-Core provides expertise for studies requiring reprogramming, characterization and genome editing of human induced pluripotent stem cells (iPSCs) and their progeny derived from IDD patients. Therefore, a major feature of the CTP Core is investigator access to both classic and modern analytical techniques using human tissue, in vivo model systems such as mouse, rat, drosophila, and in vitro assays such as 3-dimensional brain organoids and neurons and glia derived from human iPSCs. The ultimate goal of the CTP Core is to forge new avenues to improve the behavioral outcomes of IDD by correcting brain function and restoring various motor and cognitive functions. The availability of major equipment such as transmission and two-photon microscopes, existing effective workflow of services, and the collective experience with many disease models highlight the arsenal of tools available to BCM IDDRC investigators.

智力和发育障碍 (IDD) 很常见，对儿童健康具有毁灭性影响世界各地。不幸的是，绝大多数 IDD 没有有效的治疗方法，我们的对大多数 IDD 的致病机制的了解并不完整。解决问题的一大障碍如何更好地治疗 IDD 是我们对每种 IDD 如何影响细胞和组织的了解有限的。作为一个针对这个问题，我们组装了细胞和组织发病机制核心（CTP Core）研究大脑解剖学及其相关病理学是如何产生的。我们的指导思想是，解决大脑如何典型发育中的结构连接将使我们处于一个理想的位置，以揭示错误的大脑回路最终破坏 IDD 执行不同行为的能力。事实上，病理后果改变大脑发育通常表现为儿童严重的运动或认知困难。的目标 CTP Core 旨在为我们的 IDDRC 研究人员提供综合病理学的集中资源组织检查、高分辨率双光子和共焦成像、电子超微结构跟踪显微镜复制，以及与相关的人类疾病细胞模型的生成和表征国际长途电话。通过将人类细胞模型（例如 iPSC 衍生的神经元或神经胶质细胞）与深层结构和通过对不同疾病或疾病模型中大脑如何错误连接的功能表型进行分析，CTP 核心将提供了一个独特的机会来解决不同的遗传和环境因素如何影响大脑并导致细胞结构、连接性和功能的改变。为了实现这些目标，我们有将 CTP 核心分为三个并行运行的子核心，但其共同目标是解决大脑问题结构与功能和疾病的关系。神经病理学子核心提供神经元方面的专业知识从基础组织学和透射电子显微镜到深入的电路分析的组织分析；这显微镜子核心提供最先进的共焦和双光子显微镜的访问和培训；人类疾病细胞模型子核心为需要重新编程的研究提供专业知识，人类诱导多能干细胞 (iPSC) 及其后代的表征和基因组编辑来自 IDD 患者。因此，CTP Core 的一个主要特点是调查员可以访问经典的以及使用人体组织、体内模型系统（如小鼠、大鼠、果蝇）的现代分析技术，以及体外测定，例如源自人类 iPSC 的 3 维脑类器官以及神经元和神经胶质细胞。 CTP 核心的最终目标是开辟新途径，通过以下方式改善 IDD 的行为结果：纠正大脑功能并恢复各种运动和认知功能。主要的可用性透射和双光子显微镜等设备、现有有效的服务工作流程以及许多疾病模型的集体经验凸显了 BCM IDDRC 可用的工具库调查人员。