Vision statement: Identifying genes and pathways that modulate tau toxicity in FTD

The overall goal of our Center is to elucidate mechanisms of tau toxicity to drive the discovery of new therapeutic targets and biomarkers, in part through identifying genetic modifiers of tauopathy. With the exceptional collection of resources and technological advancements developed by our Project and Core leaders and thus available to our research team, the transformative studies proposed could only be possible within our Center. For example, as University of Pennsylvania and Mayo Clinic provided the greatest source of postmortem tissue from patients with progressive supranuclear palsy (PSP) for whole-exome sequencing analysis, Project 1 and Core C are ideally situated to determine how genetic variants influence pathologic burden, as well as assess the impact on gene expression and/or functional changes in the same cases for which sequencing data are available. The development of an AAV-based model of tauopathy at Mayo Clinic provides the capability to identify novel genetic modifiers in the Collaborative Cross and Diversity Outbred strains in Project 2, an endeavor that could only be successfully accomplished through a collaborative partnership between Mayo Clinic and Jackson Laboratory, combining expertise in tau pathophysiology, animal modeling, genetics and computational biology.