Development of Distinct Areas in the Human Cerebral Cortex - PROJECT SUMMARY The objective of this proposal is to gain a deeper understanding of the genetic programs that give rise to the development of specialized areas within the human cerebral cortex. Abnormalities in cortical development can lead to a wide range of neurodevelopmental disorders, which often affect different cortical areas differently. Despite of its significance, the process by which specialized areas develop remains poorly understood. This proposal aims to address this gap of knowledge by studying primary tissue and human stem cell-derived brain organoids. The first aspect of the research will utilize spatially resolved transcriptome analysis to examine human fetal cortex samples from multiple areas and embryonic ages, to identify the genes that are involved in area-specific neuronal fate specification. The second part will focus on developing the method for inducing areal identities in human brain organoids by pharmacological manipulation of signaling pathways, serving as a model for how morphogens induce area-specific cell fates in vivo. The proposed aims are attainable due to the strong background of the candidate and supportive environment provided by the mentor’s laboratory and the institution. The anticipated outcome of this research will be new insights into the principles of human cortical development, which could shed light on the etiology of neurodevelopmental disorders and ultimately transform our understanding of cortical development in health and disease. The candidate’s career goal is to become an independent researcher in an academic institution, leading a research program that utilizes human stem cell models and neurogenetics approaches to study neurodevelopmental disorders. The candidate’s prior research in the development and application of organoids as model for human brain development and diseases sets a strong foundation. The proposal outlines a comprehensive plan for scientific and professional growth that encompasses hands-on training, didactics, and mentorship. Key scientific training goals include acquiring expertise in single-cell bioinformatics, spatial transcriptomics, disease genetics analysis, and conducting rigorous optimization of organoid protocols. Additionally, the candidate will engage in structured trainings in career development to facilitate independence. The candidate will be mentored by Dr. Christopher Walsh, a renowned neuroscientist who has mentored dozens of successful independent investigators. The candidate will also benefit from the support of an advisory committee with complementary expertise. The mentored phase of the proposal will take place in the laboratory of Dr. Walsh at Boston Children’s Hospital and Harvard Medical School, known for providing exceptional research and training environments. The proposed training and research will provide the candidate with the necessary resources and support to establish a thriving independent research program.
