Research

Endogenous expression of the DUX4 transcription factor in cultured FSHD muscle cells
Endogenous expression of the DUX4 transcription factor in cultured FSHD muscle cells.

The Tapscott Lab studies gene transcription in a chromatin context in normal development and disease, with special emphasis on the molecular mechanisms of cell specification and differentiation. Recent work has focused on the transcription factor DUX4 and related proteins and their role in regulating early pluripotent stem cell specification, development, and disease, including cancer and muscular dystrophy. In addition, the lab studies the molecular and genomic regulation of cell specification using myogenesis and neurogenesis as model systems.

Projects

Wellstone Muscular Dystrophy Specialized Research Center (Seattle) (PI: Chamberlain)
Sponsor: NIH/NIAMS
Award Number: 2 P50 AR065139
Award Dates: 07/01/2018 – 06/30/2023

This proposal addresses the remaining barriers to successful clinical trials in common forms of muscular dystrophy. Specifically, it improves the function of potentially curative gene therapy approaches and identifies measurements that will determine whether the clinical trials result in beneficial results. Project 2 will identify the measurements necessary to conduct rigorous and efficient therapeutic trials in facioscapulohumeral dystrophy (FSHD). Specifically, it determine the value of MRI characteristics and candidate molecular biomarkers for predicting disease activity and progression.


Regulation and activity of the DUX4 transcription factor (PI: Tapscott)
Sponsor: Friends of FSH Research and the Chris Carrino Foundation for FSHD
Project Dates: 05/15/2018 – 05/14/2022

This award supports the Tapscott Lab’s high-impact studies on FSHD research in identifying biomarkers for disease activity and progression, generation of mouse models for therapeutics studies, and training of new investigators.


Why is Skeletal Muscle Tumor Suppressive? (PI: Ghajar)
Sponsor: W.M. Keck Foundation
Project Dates: 07/01/2017 – 06/30/2020

Using skeletal muscle (SkM) as a model of infertile soil, we propose a series of experiments at the biological and technological cutting edge to specify the molecular mechanisms by which SkM suppresses metastasis. Our goal is to test whether ectopic expression of SkM-derived metastasis suppressors prevents colonization of susceptible sites.


D4Z4 Coding Transcripts and FSHD (PI: Tapscott)
Sponsor: NIH/NIAMS
Award Number: 5 R01 AR045203
Project Dates: 02/15/2016 – 12/31/2020

The proposed research will determine the portion of DUX4-induced pathophysiology conserved in mice and establish a human-derived preclinical model for studying the primate-specific aspects of DUX4-induced pathophysiology. The aims will determine the cause of DUX4 toxicity in human cells and the opportunities and limitations of studying these pathways in mouse cells, and develop a preclinical model of FSHD by improving the xenotransplantation of human muscle progenitor cells into mice.


The Pathogenesis of Facioscapulohumeral Muscular Dystrophy (PI: Tapscott)
Sponsor: NIH/NINDS
Award Number: 5 P01NS069539        
Project Dates:  09/30/15 – 09/29/20       

The research proposed under this program project grant combine genetic, epigenetic, transcriptional and developmental approaches to defining the epigenetic modifications associated with FSHD. Together they will determine whether repeat-mediated epigenetic silencing and repetitive element expression represent specific pathways that can be targeted for therapeutic intervention in FSHD. Results from this research will provide the basis for clinical therapeutic trials in FSHD.


SMCHD1 Pathways as Candidate Targets for FSHD (PI: Tapscott)
Sponsor: NIH/NIAMS
Award Number: 5 R01 AR066248
Project Dates: 04/25/2014 – 03/31/2019

The proposed research will identify the fundamental molecular mechanisms that epigenetically repress the D4Z4 region through the production, modification, stability and interacting partners of SMCHD1. The health relevance of this research is that the failure of these mechanisms results in facioscapulohumeral muscular dystrophy and the proposed studies will provide the basis for future therapeutic development.


Lineage Determination in Muscle (PI: Tapscott)
Sponsor: NIH/NIAMS                                         
Award Number: 5 R01 AR045113
Project Dates: 05/01/13 – 04/30/19 (NCE) 

The major goal of this project is to determine the relative genetic and epigenetic roles of transcription factors in specifying the myogenic lineage.