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Dr Phadke is affiliated to the Department of Molecular Neuroscience at ION and the Dubowitz Neuromuscular Centre at ICH/GOSH.
The main research interest of our group involves studying the expression and regulation of genes and proteins in neuromuscular disorders, particularly congenital myopathies and congenital muscular dystrophies. We are interested in developing novel quantitative assays and imaging techniques for routine diagnostic use, pathological phenotyping of animal models of NMDs, and outcome measures in clinical trials. Key projects currently underway include:
· Dystrophin as a biochemical outcome measure in Duchenne muscular dystrophy clinical trials: the DNC labs at ICH and ION have developed a high-throughput automated digital method for quantifying dystrophin. This will be essential in monitoring the biochemical outcome in therapeutic trials of AONs that are able to induce exon skipping and restore the transcript reading frame that is disrupted in DMD
· We have developed a high throughput automated digital script for muscle fibre size analysis in biopsies. Using this method we are currently analysing a large cohort of clinically and/or pathologically normal/minimal change biopsies to produce age-stratified normative data for muscle fibre size from 0-16 years. We are further developing a bright-field myosin heavy chain multiplex IHC assay that will provide fibre-type specific age-stratified data.
· In collaboration with Professor Gaspar at ICH whose group is looking at the translational potential of lentiviral mediated GAA expression using genetically modified haematopoetic stem cells in GAA deficient mice, we are characterising the pre- and post treatment pathology in these mice, using a combination of digital automated scripts and multiplex IHC.
· Over the last two years we have developed expertise in characterisation of muscle pathology in human biopsies and rodent models of critical illness, collaborating with a group of investigators and clinicians who are interested in understanding the pathomechanisms and pathways that cause muscle wasting in critical illness (Professor Singer, Dr Puthucheary). In one study, we showed for the first time that myofasciitis is a key element of the tissue pathology preceding and accompanying myonecrosis in critically ill patients, and can be detected non-invasively. The functional implications of these findings will be explored in future studies. In another study, we developed a high-throughput quantitative script for measuring COX-SDH intensity as a surrogate marker for mitochondrial biogenesis induced by exercise in mildly septic rodents in a complex, mixed-fibre type muscle like the gastrocnemius.
In the current year (2016) we have initiated a multilaboratory project that will aim at exploring applications of multiplex IHC in brightfield, fluorescent and spectral imaging in muscle biopsies for developing novel diagnostic assays in human biopsies and quantitative pathological outcome measures in rodent models of NMDs (in collaboration with Roche Diagnostics, Perkin-Elmer, BORL, and UCL/ICH/Imperial partners).