Cellular and Tissue Pathogenesis

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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.