Cellular and Tissue Pathogenesis

智力和发育残疾是常见的，对儿童健康有着毁灭性的影响 世界各地不幸的是，对绝大多数IDD没有有效的治疗方法， 对大多数IDDs的致病机制的认识尚不完全。解决这一问题的主要障碍 如何更好地治疗IDD是我们对每种IDD中细胞和组织如何受到影响的有限知识。作为 针对这一问题，我们组装了细胞和组织发病核心（CTP核心）， 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 结构是有线在典型的发展将使我们在一个理想的位置，以揭示如何错误的大脑电路 最终破坏IDDs执行不同行为的能力。事实上， 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核心是为我们的IDDRC研究者提供一个集中的资源， 组织检查，高分辨双光子和共焦成像，电子显微镜超微结构跟踪 微拷贝，以及与以下相关的人类疾病细胞模型的生成和表征： IDDs.通过将人类细胞模型，如iPSC衍生的神经元或神经胶质细胞，与深层结构和 CTP核心将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， 提供了一个独特的机会，以解决如何独特的遗传和环境因素可能会影响大脑 并导致细胞结构、连通性和功能的改变。为了实现这些目标，我们 我把CTP核心分成三个子核心，它们并行工作，但共同的目标是解决大脑问题。 结构，因为它与功能和疾病有关。神经病理学子核心提供神经元 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; 显微镜子核心提供访问和培训，以国家的最先进的共聚焦和双光子显微镜; 人类疾病细胞模型子核心为需要重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核心的一个主要特点是调查人员可以访问两个经典的 以及使用人体组织，体内模型系统如小鼠，大鼠，果蝇， 以及体外测定，例如源自人iPSC的3维脑类器官和神经元和神经胶质。 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。主要的可用性 设备，如透射和双光子显微镜，现有的有效工作流程的服务，以及 许多疾病模型的集体经验突出了CIDDRC可用的工具库 investigators.

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.