RVC PhD: Rebalancing mitochondrial metabolism in Duchenne Muscular Dystrophy - a novel therapeutic avenue?

Duchenne muscular dystrophy (DMD) is a fatal X-linked muscle wasting disease caused by mutations in the DMD gene that lead to the loss of a functional version of the subsarcolemmal protein dystrophin. There are no currently available treatments that prevent the inexorable loss of muscle function associated with muscle fibre loss and fibrosis; synergistic, combinatorial therapies represent an urgent clinical unmet need. Mitochondria not only produce the majority of ATP required for efficient cell function, but also act as regulators of calcium influx and mediators of cell death. Impaired mitochondrial function and calcium buffering as well as increased oxidative stress are early events in the pathogenesis of DMD, both in humans and in the mdx mouse model, which mimics key features of DMD. Furthermore, such metabolic imbalance activates the metabolic sensor AMP-activated protein kinase (AMPK) and pharmacological interventions targeting AMPK are reported to improve skeletal muscle metabolism and function in this DMD model.

The goal of this work is to determine whether DMD-mediated mitochondrial dysfunction can be alleviated by specific activation of AMPK. The project will define the molecular components of the aberrant mitochondrial fission, fusion and mitophagy responses leading to metabolic impairment in the skeletal muscle of the mdx mouse. In addition, a transgenic mdx mouse model will be generated in which AMPK is activated specifically in skeletal muscle, to evaluate AMPK-mediated protective mechanisms targeting the mdx metabolic profile.

To achieve these aims, the student will become proficient in a variety of molecular and cell biology techniques (cell culture, co-immunoprecipitation, western blot, qRTPCR, biochemical assays including cellular respiration, cell death and mitochondrial morphology), imaging (live imaging, confocal microscopy, histology/immunofluorescence), in vivo techniques (generation/characterization of a unique transgenic mouse model), and muscle physiology (including exogenous gene transfer).

Data generated from this project will not only advance the basic science field but will assess the potential for specific AMPK modulators as novel therapeutics for DMD.


- Essential Requirements -
-Applicants must hold, or expected to achieve a first or upper second-class undergraduate honours degree or equivalent, or an MSci or Masters in a relevant subject.
-Enthusiasm, motivation and scientific curiosity
-Previous lab-based project/work experience (at least 6 months)

- Desirable Requirements -
-Previous experience with mouse models, ideally holding a Home Office license
-Background in mitochondrial biology and/or Muscular Dystrophy