We are seeking postdoctoral fellows to study the molecular mechanisms underlying neuromuscular phenotypes and develop genetic-based therapeutic approaches. These positions are funded by Cure-CMD and AFM-Telethon, two patient-driven organizations with a long history of supporting innovative therapeutic approaches in neuromuscular diseases. The fellows will be working in a team led by Dr. Dwi U. Kemaladewi at the UPMC Children’s Hospital of Pittsburgh (https://kemaladewilab.com).
Project Description and Environmental Support:
Muscular dystrophies impact an estimated 250,000 patients in the United States, resulting in an annual medical expenditure of over $46 billion. The economic loss is more substantial in the congenital-onset muscular dystrophies (CMDs) due to patients’ inability to enter the workforce and/or their premature death. LAMA2-deficient congenital muscular dystrophy (LAMA2-CMD), the most common form of CMD, is caused by mutations in the LAMA2 gene encoding the LAMA2 protein. The lack of LAMA2 protein causes degeneration of skeletal muscle and impaired Schwann cell myelination. Patients are provided with disease symptom managements, but there is no curative option.
Owing to the genetic nature of the disease, mutation correction would be a promising treatment for LAMA2-CMD. We have used CRISPR/Cas9 to correct a splice site mutation in the Lama2 gene and showed amelioration of disease phenotypes in a LAMA2-CMD mouse model (Kemaladewi et al, Nat Medicine, 2017). However, the mutation heterogeneity identified in patients significantly hampers future clinical translation. In contrast, targeted modulation of the expression of disease modifier genes would be beneficial to all individuals affected with LAMA2-CMD. We developed a CRISPR activation-based approach to postnatally upregulate a disease modifier gene Lama1, which is structurally and functionally similar to Lama2, as a potential mutation-independent approach for LAMA2-CMD (Kemaladewi, Bassi, et al, Nature 2019). The ongoing efforts in our lab involve preclinical evaluations of the efficacy and safety profiles of the CRISPR activation strategy in mouse models and patient-derived cells.
The University of Pittsburgh and UPMC Children’s Hospital of Pittsburgh, rank in the top 5 of NIH funding and top 10 of Best Children’s Hospitals in the nation, offer intensive and collaborative biomedical research environment. In-house core facilities provide state-of-the-art technologies, including animal and cellular imaging, AAV production, metabolic and genomic analyses, flow cytometry and many more. Our lab is equipped with dedicated instruments to assess neuromuscular functions in small animals.
Candidate must have (or be near to completing) a PhD, with a proven track record of successful training as demonstrated by first author publication(s). We are looking for a highly motivated and interactive colleague with background in genetics/neuroscience and mouse model of disease. Experience in experimental therapeutics (siRNA, antisense oligonucleotides, CRISPR/Cas, viral vectors) would be desirable. Interested applicants should submit a complete CV, a description of their research interests and career goals, and the contact details of three referees to: email@example.com.
Only shortlisted candidates will be contacted and invited for interviews. Application review will begin immediately and continue until the positions are filled.