Molecular drivers of tauopathies in stem cell models from diverse human populations

Project Summary/Abstract The overall goal of this research and training plan is to define the molecular mechanisms underlying tauopathies in diverse populations. Currently, the contribution of specific MAPT mutations to tau toxicity, the mechanisms by which tauopathies occur, and the contribution of different genetic backgrounds to these mechanisms remain poorly understood. This project aims to define druggable molecular signatures of MAPT mutations using stem cell models from African (Nigeria), Asian (Japan), and South American (Brazil) populations. The investigator, Dr. Miguel Minaya, will gain advanced training in stem cell biology and functional genomics in support of an innovative approach that establishes novel cell models that use human induced pluripotent stem cell (iPSC)-derived neurons, diverse populations, and CRISPR-based screens to study the extent to which MAPT mutations occurring in diverse genetic backgrounds will produce common and/or unique molecular signatures of disease. The mentors who were selected for this training, Drs. Celeste Karch, Carlos Cruchaga, and Martin Kampmann, are internationally recognized experts in the fields of tau biology, human and molecular genetics, stem cell biology, genome editing, and functional genomic screens using CRISPRi. The goal of this proposal is to define druggable molecular signatures of MAPT mutations using stem cell models from diverse populations. The overarching hypothesis of this proposal is that MAPT mutations occurring in diverse genetic backgrounds will produce common molecular signatures of disease. To define these common mechanisms, I will define molecular changes in iPSC-derived neurons from iPSC lines with engineered MAPT mutations and will then functionally annotate those genes using CRISRPi screens. Through this research and mentored training plan, Dr. Minaya will make fundamental contributions to our knowledge of the mechanisms by which disruptions in the MAPT gene are associated with tauopathies and will establish new experimental tools and approaches that will form the foundation for a career as an independent, translational neuroscientist.