# Identifying genes and Pathways that impact Tau Toxicity in FTD

> **NIH NIH U54** · MAYO CLINIC  JACKSONVILLE · 2020 · $1,216,084

## Abstract

PROJECT SUMMARY/ABSTRACT
In this highly-integrated and multi-disciplinary Center without Walls entitled “Identifying genes and pathways
that modulate tau toxicity in FTD”, we seek to discover novel genetic modifiers of tauopathy to provide
unique insight into disease mechanisms, as well as support the development and validation of an innovative
approach to measure tau burden in patients using plasma samples. Taking advantage of the genome
sequencing data available from PSP patients, Project 1 will identify genetic variants that influence disease risk,
and in collaboration with the Human Biology Validation Core determine how key variants are associated with
tau burden. As a complementary but alternative approach to identify genetic modifiers, Project 2 will utilize the
Collaborative Cross and Diversity Outbred mouse strains developed at Jax Labs to uncover genetic variants
that determine sensitivity or resistance to AAV-induced tauopathy. Project 3 will investigate the hypothesis that
assessment of plasma tau levels following the administration of anti-tau antibodies provides a sensitive and
specific biomarker for tau aggregation in the brain, employing samples from both murine models of tauopathy
as well as patients enrolled in ARTFL and LEFFTDS. Project 4 will construct a disease signature for FTD-tau
and mine public databases and systems analyses to predict pharmacologic and/or genetic interventions to
reverse the signature, as well as elucidate how genetic modifiers identified in Projects 1 and 2 impact tau
metabolism and secretion. The four research projects will be supported by the Administrative Core (Core A),
the Viral Production and Cloning Core (Core B), the Human Biology Validation Core (Core C), and the Data
Coordination Core (Core D). We envision that at the conclusion of the funding period, we will have: (i) identified
key genes that determine either sensitivity or resistance to tau-mediated neurodegeneration; (ii) developed a
sensitive and specific blood-based biomarker for tau deposition in the brain; (iii) discovered novel therapeutic
targets predicted to reverse the transcriptional signature that defines tau mutation carriers; and (iv) determined
how tau mutations and genetic modifiers of tauopathy impact tau metabolism, protein homeostasis and cell
viability. Therefore, our Center is uniquely poised to enable the identification of patient populations at risk,
while simultaneously enhancing diagnostic capabilities and expanding therapeutic possibilities.

## Key facts

- **NIH application ID:** 10012947
- **Project number:** 5U54NS100693-05
- **Recipient organization:** MAYO CLINIC  JACKSONVILLE
- **Principal Investigator:** LEONARD PETRUCELLI
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,216,084
- **Award type:** 5
- **Project period:** 2016-09-30 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10012947

## Citation

> US National Institutes of Health, RePORTER application 10012947, Identifying genes and Pathways that impact Tau Toxicity in FTD (5U54NS100693-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10012947. Licensed CC0.

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