Generation and molecular characterization of multiple human neural cell types

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SUMMARY – Scientific Core Human induced pluripotent stem cells (iPSCs) offer a remarkable opportunity to study human tissue and organ development and to discover the molecular and cellular basis of human diseases. Capable of being differentiated into nearly any cell type in the human body, iPSCs have proven to be invaluable for studying previously inaccessible cell populations such as neural cells of the developing and mature brain. These populations are among the most relevant cell types in the study of neurotropic viruses such as Zika virus (ZIKV) and West Nile virus (WNV). ZIKV, a mosquito-borne flavivirus, is currently reported to be circulating in 26 countries and territories in Latin America and the Caribbean. While ZIKV infection has been linked to microcephaly in newborns and other brain abnormalities such as Guillain-Barré syndrome, how ZIKV impairs brain development and function is unknown. WNV, another member of flavivirus genus, can also lead to serious neurologic illnesses such as encephalitis or meningitis, with the underlying mechanism remains elusive and there is no reported studies using human cellular models. Since access to human brain tissue is very limited, generating new cellular models using human iPSCs can facilitate biological discovery and drug development. Recently developed technology to generate 3D cerebral organoids from iPSCs holds the promise of allowing for more accurate models that recapitulate key processes and features of human brain development. To model ZIKV and WNV infections of the central nervous system, the Scientific Core will optimize and standardize protocols for differentiation of disease-relevant specific cell types (Specific Aims 1 and 2), generate genetically-modified iPSC lines for functional studies (Specific Aim 1), supply cells and provide on-site training for all projects (Specific Aim 2), and perform bioinformatics analyses for transcriptomic profiling (Specific Aim 3). The Scientific Core plays an essential role in setting standards for reproducible conditions for cell culture through cross-training of personnel in Projects 2 & 3, which is a critical component of robust platform development. The Scientific Core will work closely with Project 1 on technology development and protocol optimization and the Administrative Core for documentation and dissemination of validated protocols.