Cellular and Tissue Pathogenesis

细胞和组织发病机制

• 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
• 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

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(IDDS)很常见，对儿童健康有毁灭性的影响 环游世界。不幸的是，目前还没有有效的方法治疗绝大多数的IDDS和我们的 大多数IDDS的发病机制尚不完全清楚。解决问题的主要障碍 如何更好地治疗IDDS是我们对每个IDD中细胞和组织如何受到影响的有限了解。作为一名 直接回应这个问题，我们已经组装了细胞和组织致病核心(CTP核心)来 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 结构在典型的发展中是连线的，这将使我们处于一个理想的位置，以揭示大脑电路是如何发生故障的 最终破坏在IDDS中执行不同行为的能力。事实上，这种疾病的病理后果 儿童大脑发育的改变通常表现为严重的运动或认知障碍。的目标是 CTP的核心是为我们的IDDRC研究人员提供一个集中的全面病理资源 组织检查、高分辨率双光子和共聚焦成像、超微结构电子跟踪 显微镜，以及与以下相关的人类疾病细胞模型的产生和表征 IDDS。通过将人类细胞模型，如IPSC来源的神经元或胶质细胞，与深层结构和 CTP Core将对大脑在不同疾病或疾病模型中如何错误连接的功能表型进行研究 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核心划分为三个并行运行的子核，但有一个共同的目标是解析Brain 结构，因为它与功能和疾病有关。神经病理学分科提供神经学专业知识。 从基本组织学和透射电子显微镜到深入电路分析的组织分析； 显微镜分核心提供对最先进的共焦和双光子显微镜的访问和培训； 而人类疾病细胞模型分核心为需要重新编程的研究提供专业知识， 人诱导多能干细胞及其后代的特性和基因组编辑 来源于IDD患者。因此，CTP核心的一大特点是调查人员可以访问这两个经典 使用人体组织的现代分析技术，活体模型系统，如小鼠，大鼠，果蝇， 以及体外分析，如来自人IPSCs的三维脑器官、神经元和神经胶质细胞。 CTP核心的最终目标是通过以下方式建立新的途径来改善IDD的行为结果 纠正大脑功能，恢复各种运动和认知功能。主要产品的可用性 传输和双光子显微镜等设备，现有有效的服务流程，以及 对许多疾病模型的集体经验突出了BCM IDDRC可用的各种工具 调查人员。