Research

Our multi-disciplinary, team-based research is comprised of three Cores and two Projects, working together to understand the multiple nodes of tau metabolism and pathobiology.

How the Projects & Cores Interact

Our FTD CWOW is structured to enable researchers to systematically identify, test, and share novel insights across multiple institutions. By synergizing our research efforts and creating opportunities for substantive scientific interactions, the Center creates an efficient pipeline for assessing the functional impact of variation in tau metabolism genes that may promote risk for tauopathy.

Our unique team of experts in distinct, complementary disciplines will allow for highly synergistic interactions, where the whole will be much greater than the sum of the parts.

 

CWOW Organizational Figure
LEGEND

#1: Mutants, PTMs, Structures
#2: SNPs, Risks, Functional Data
#3: Structures, Fragments
#4: SNPs, Risks, Functionality

CWOW Cores

CORE A: Administrative and Data

Lead: Aimee Kao, MD, PhD
Co-Lead: Jennifer Yokoyama, PhD

The Administrative and Data Core will provide overall coordination, leadership, scientific insight, and support for our Center activities and projects. We will oversee our public facing website, share resources to the scientific community, and serve as an internal data sharing and management hub for the Center. Our team will facilitate and coordinate between the University of California San Francisco (UCSF) and Washington University in St. Louis (WashU) teams, ensuring effective communication and forward progress towards all Center goals.

CORE B: Macromolecular and Cellular Structure

Lead: David Agard, PhD

The Macromolecular and Cellular Structure Core will provide cutting edge and innovative platforms for structural characterization of discoveries made by our Center. Our goals are to investigate how tau is stabilized by molecular chaperones and how it is channeled for degradation by the lysosome. Together, the contributions from our Core will reveal fundamental mechanisms dictating tau turnover and provide novel targets for potential therapeutic intervention.

CORE C: Genomics and Transcriptomics

Lead: Jennifer Yokoyama, PhD
Co-Lead: Efstathios Gennatas, PhD

The Genomics and Transcriptomics Core will provide foundational information regarding variation in tau metabolism pathway genes and support the genomics and transcriptomics needs of our Center. Our Core will establish and create innovative tools to be used by the broader research community. We will develop a ‘Tau Polygenic Risk Score’ (TPRS) that will be used to stratify samples for genetic risk for tau-mediated neurodegeneration. Gene candidates nominated by our CWOW projects will be integrated into an informational and interactive database called the ‘Tau Metabolism and Variant database’ (TMVdb). The contributions from our Core will give a better understanding of how human genetic variation contributes to tau metabolism and homeostasis.

CWOW Projects

PROJECT 1: Studying Tau Chaperones, Targeting, and Proteolysis

Lead: Aimee Kao, MD, PhD
Co-Lead: David Agard, PhD

This project will focus on upstream aspects of tau metabolism and homeostasis.

Through our systematic study of how tau metabolism changes with gene variants and disease, we can better comprehend the molecular perturbations predisposing to tauopathy. This could lead to strategies to improve tau clearance for the treatment and prevention of FTLD-tau.

PROJECT 2: Studying Tau Half-life and Secretion

Lead: Celeste Karch, PhD

This project will focus on downstream aspects of tau metabolism and homeostasis.

This project will reveal novel mechanisms underlying tauopathy that are driven by specific tau proteoforms and whether therapeutics designed to block specific tau proteoforms impact pathologic events.

 

This U54 A138178 grant is funded by the National Institutes of Health (NIH), the National Institute on Aging (NIA), and the National Institute of Neurological Disorders and Stroke (NINDS)