Novel Therapeutics for FSHD - Resources Core - Core C

项目总结

PROJECT SUMMARY The Resources Core will provide cell, animal model and bioinformatic reagents, resources, and databases to support the Wellstone research projects as well as the greater FSHD and muscular dystrophy research communities. The Resources Core will continue to build a major biomaterials repository of biopsies and cells from FSHD patients and their first degree family members, with a focus on FSHD families with non-manifesting subjects (Aim 1). Patient-derived, low passage CD56+ muscle cells and reprogrammed iPSC myogenic lines will be a resource for validation of modifier genes identified in genomic clinical studies in Project 1 and in DUX4 pathway studies and in drug discovery and validation studies in Projects 2 and 3. Myogenic cells from FSHD family cohorts will continue to be distributed to FSHD researchers and industry collaborators to support statistically powered studies with clinically and genetically validated cell lines. The Resources Core will become a new resource for our newly developed Wellstone FSHD animal models to enable animal drug studies, and be a resource for molecular, histopathology and physiology assays of FSHD muscle pathology in animal and cell models. Wellstone FSHD animal models include: 1) DUX4 injection and DUX4-inducible zebrafish models enable rapid drug and morpholino testing to investigate developmental and tissue-specific mechanisms of DUX4 toxicity (Aim 2); 2) a tamoxifen-inducible conditional DUX4 transgenic mouse that is a first-of-its-kind tightly controlled DUX4 inducible FSHD mouse model that expresses a heritable DUX4 transgene and displays inducible myopathy and pathophysiology, ideal for testing of candidate FSHD drugs (Aim3); 3). DUX4 zebrafish and mouse models will be used to investigate FSHD modifier genes identified in Projects 1, 2 and 3, and to test posttranslational, hypoxia and HA signaling pathway inhibitors in Projects 2 and 3. FSHD muscle xenografts provide a unique FSHD animal model enabling investigations of drugs and ASOs that block DUX4 function in a highly humanized, vascularized and innervated FSHD muscle, not achieved with standard cell xenografts (Aim 4). The FSHD xenograft muscle model will be used for optimizing ASO knockdown of DUX4 and testing 4-MU and candidate HA and hypoxia signaling drugs in Projects 2 and 3. A bioinformatics and statistical core will continue to be responsible for managing databases of integrated clinical and experimental data, performing bioinformatic and statistical analyses of data generated in all Projects, planning well- designed, statistically powered studies for all Projects, and supporting GWAS and DNA methylation analyses, including comparison to existing Wellstone data for Project 1 and RNA-Seq data analysis of ASO studies in Project 3 (Aim 5). Availability of Core resources will be disseminated via the Wellstone Center website and through presentations at FSHD patient and research meetings.