Sunday, March 16, 2025
3/16/2025
Project Summary/Abstract Tau, coded for by the gene MAPT, can aggregate in the brain and is associated with many neurodegenerative diseases. Evidence suggests that the level of expression of MAPT (tau) can be genetically associated with disease risk. Furthermore, simply reducing the level of tau may be beneficial. There are many ways this may be done, but one drawback of current approaches has to do with drug delivery. The brain can be difficult to reach with therapeutics effectively, and some therapies for the brain can require invasive procedures that are not ideal for a vulnerable population such as for individuals with neurodegenerative diseases. So, it may be better to find a way to reduce tau with something that could be used in pill form, or a small molecule drug. One way to affect tau levels with a small molecule drug may be to target transcriptional networks involved in MAPT expression. There is now data available on the cis-regulatory environment around the MAPT gene that provides information on how MAPT is expressed in the central nervous system. What controls this process, though, are trans- regulatory elements such as transcription factors. The field does not yet know what these key transcription factors are. This proposal would use the most comprehensive technologies available to find out which transcription factors control expression of MAPT. Once these transcription factors are known, it may be possible to find a way to target them therapeutically by developing or modifying drugs that affect their function, or specific drugs that affect the interactions between transcription factors needed for MAPT expression. In this study, the investigators will: (1) Identify transcription factors that, when activated or repressed, can modulate the transcription level of MAPT using CRISPRi/a screens with follow-up validations, (2) Determine which trans-regulatory elements are directly associated with the MAPT promoter (either directly or through cis-regulatory element looping) using proteomic approaches, and (3) Determine targetability of candidate transcription factors affecting MAPT expression by assessing their genome wide and cell type–specific binding profiles, expression, and variability level between AD cases and controls. Using these approaches provides a clear direction for comprehensively understanding the trans-regulatory elements needed for MAPT expression supported by a combination of unbiased and hypothesis-driven approaches. These data will support new approaches to target MAPT expression therapeutically by targeting transcriptional networks responsible for its expression while also assessing cell type specificity, off-target effects, and disease state relevance. The principal investigators include leaders in the gene regulation field (Myers), tau biology and MAPT cis-regulatory elements (Cochran), and mass spectrometry, including in application to tau biology (Swaney). The orthogonal approaches proposed in this study will provide a foundational dataset of the comprehensive landscape of trans-regulatory elements controlling expression of MAPT and will provide new avenues to pursue for treatment of tauopathies.
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