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Human Stem Cell Neurophysiology Laboratory

Michael W. Nestor, Ph.D., Investigator

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Autism Spectrum Condition (ASC) is a complex genetic disorder that has lacked a human cell-based platform that incorporates the heterogeneity of the disease.  Such a platform would assist identification of potential therapeutic compounds. Human induced pluripotent stem cells (iPSCs) represent an unparalleled technology for modeling aspects of ASC while capturing its genetic heterogeneity.

Stem_cell1An important hypothesis put forth to explain the behavioral challenges observed in individuals with ASC suggests that there is a significant imbalance in the excitatory and inhibitory inputs in the brain. The connections between excitatory and inhibitory neurons are made in cortical circuits early in development, and there is ample evidence that the genesis and maintenance of these circuits requires a number of different cell types as well as the complex interactions between these cells within 3-dimensional (3D) tissue.  Although models of ASC-associated conditions have been established by reprogramming patient somatic cells into iPSCs, these models have been developed using two-dimensional (2D) tissue culture conditions and typically with only one neuronal cell type. In order to improve the robustness and utility of iPSC models of ASC we have developed a novel 3D iPSC culture system that recapitulates some aspects of early human cortical development. This system produces interneurons and excitatory neurons in developing cortical circuits. We hypothesize that the use of this 3D system will allow us to more accurately reflect dysfunctional circuitry in ASC and model the interaction between excitatory and inhibitory inputs.

By making 3D stem cell cultures from individuals with ASC with known genetic variants and studying the development of these circuits and inputs, we will elucidate mechanisms that are in place early in the disorder during critical times of development, and we will identify novel biomarkers and points of intervention for ASC not uncovered by traditional 2D iPSC models.

Stem_cell2Additionally, we use high-throughput physiological assays (multi-electrode arrays, real-time calcium imaging, optogenetics, high-content cellomics-based morphological assays) combined with next-generation molecular biology (RNAseq, CRISPR, dqPCR, Illumina ChIP-Seq) to understand the role of genetic mutations in the function of iPSC-derived neurons from individuals with ASC, providing pathways to develop drug screens should candidates arise. Finally, because our iPSC lines come from individuals that are extensively clinically and genetically characterized we will be able to understand more clearly the connections between molecular pathways and cell biology in the context of ASC using our 3D iPSC system. This work is important for the development of a robust ASC iPSC model that will be used as a platform for preclinical drug discovery in order to find early treatments and enhance the lives of people with ASC.

Lab Team

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Michael W. Nestor, Ph.D.
Investigator
Director of Neural Stem Cell Research

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Jonathan Nestor, B.S.
Senior Research Assistant
Coordinator, Neural Stem Cell Laboratory
Research interest: Application of 2D electrophoresis and mitochondrial dysfunction in ASC.

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Madel Durens, Ph.D.
Postdoctoral Research Fellow

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Omotayo Oduwole
Research Technician

Contact Information

Michael W. Nestor Ph.D.,
Investigator

Laboratory of Human Stem Cell Neurophysiology
Program in Neuroscience
Hussman Institute for Autism

801 W. Baltimore Street
Suite 301
Baltimore, MD 21201
443-860-2580 ext. 731

mnestor@hussmanautism.org

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