Dr. Vered Raz
Oculopharyngeal muscular dystrophy (OPMD) is a rare, ;autosomal dominant, late-onset myopathy. OPMD patients develop muscle weakness from midlife onwards that gradually limit mobility and independence. OPMD is recognized by the specific pattern of muscle involvement initially causing ptosis and dysphagia. During disease progression most skeletal muscles are affected. Currently, there are no medical options to prevent or delay muscle weakness in OPMD.
OPMD is caused by a germline mutation in PABPN1, a regulator of RNA processing. The mutant PABPN1 aggregates, causing a depletion in levels of functional PABPN1. We investigate the molecular mechanisms that are associated with Reduced PABPN1 levels, and our ultimate goal is to develop a therapy for OPMD.
Our research combines clinical, translational and basic research using multidisciplinary approaches. We utilize and develop different models: cellular, organoid (muscle-on-a-chip) and mouse models. We combine various genome-wide research approaches to identify molecular pathways and biomarkers that are associated with muscle aging, muscle degeneration and OPMD pathology. Our studies on targeted pathways and genes are carried out using high-throughput imaging and image quantification technologies.
How a germline mutation leads to adult-onset disorder, what protects muscle weakness during early adulthood and what are the signal that leads to the late onset? Are those similar triggers of muscle aging?
What are the regulators leading to a specific muscle involvement?
What are RNA species are involved in this pathology and what is their role in muscle biology?
Figure 1. A flowchart of research approaches in OPMD and muscle aging. We start from muscles: generate molecular data, from which we identify molecular pathways, signatures and biomarkers. We validate these observations using tissue histology, and using in vitro models. The endpoint of our studies is to develop specific therapy for OPMD and muscle aging.
PABPN1-mediated muscle pathology
Figure 2. Examples of muscle pathology in an OPMD patient, and in a tibialis anterior mouse muscle with reduced PABPN1 levels (shPab). Plots next to the images show image quantification.
PABPN1-mediated myogenesis defects
Figure 3. In vitro models: 2D- proliferating and fused muscle cell cultures in controls and PABPN1 down-regulation (shPAB), staining with structural proteins.
3D- a muscle bundle from control and shPAB cells. Right panel shows shPAB muscle bundle stained with MyHC and MURC. Expression of Actin-GFP restores the MyHC and MURC expression in the muscle bundle.