(OPEN) Postdoctoral Fellows/Research Scientists - Genetic Diversity in Muscular Dystrophy

 

The Kemaladewi Lab has multiple positions for postdoctoral fellows (experienced candidates can be employed at research scientist level) to study the impact of genetic diversity in muscular dystrophy & response to therapies. This project is supported by a highly competitive NIH Director's New Innovator Award, part of the High-Risk, High-Reward Program, to Dr. Kemaladewi and will be further strengthened with an anticipated NIH R01 grant to the Kemaladewi Lab.

The problem: Differences in our individual genomes give rise to most of human diversity, including the severity of disease presentations and responses to therapies. The development of CRISPR-based genome editing has sparked intense interest in the use of this technology for therapeutic interventions, including muscular dystrophies. Yet, the component of genetic diversity has been largely ignored in many preclinical studies. 

The approach: You will develop and use genetically diverse animal models of human diseases to identify novel genetic modifier factors. The first focus will be on congenital-onset muscular dystrophy and the evaluation of disease modifiers in neuromuscular, respiratory, and neurological phenotypes. Some efforts will also go towards an evaluation of the efficacy and safety of a variety of innovative therapeutic genome editing in genetically diverse patient samples, befitting the truly translational nature of the project and the laboratory.

 

The team: You will be a member of a young, collaborative, energetic, and international research group with a strong commitment to improve the lives of individuals affected by pediatric rare diseases, including neuromuscular and neurological disorders. The laboratory is located in the Rangos Research Building of the UPMC Children’s Hospital of Pittsburgh. In-house core facilities provide state-of-the-art technologies, including animal and cellular imaging, AAV production, flow cytometry, metabolic and genomic analyses. Our lab is equipped with dedicated instruments to assess neuromuscular functions in small animals. You will have access to full educational and professional development opportunities offered by the University of Pittsburgh School of Medicine.

Basic qualifications:

  • Ph.D. in genetics, molecular & cell biology, neuroscience, or any related disciplines. Candidate with >3 years of postdoctoral research experience may be appointed as a research scientist.

  • Demonstrated proficiency in working with mouse model of human diseases, supported by primary authorship in peer-reviewed journal(s).

  • Excellent organizational skills and a demonstrated ability to handle large phenotyping data.

  • Proficient with standard molecular biology methods including but not limited to cell culture, transfections, molecular cloning, immunoassays, and quantitative real-time PCR.

  • Creativity, self-motivation, and the ability to assimilate new information from multiple sources.

 

Preferred qualifications:

  • Experience in phenotyping/functional assays for neuromuscular and neurological diseases.

  • Experience in drug developments, including but not limited to CRISPR/Cas, viral vectors, antisense oligonucleotides, RNAi, small molecules.

  • A track record on toxicity/immunological studies of a drug candidate would be highly desirable.

 

Interested candidates should submit a cover letter describing career aspiration and potential fit to the laboratory/project, a CV and contact detail of three references to dwi.kemaladewi@chp.edu. Request for an informal discussion/inquiry is welcome.

(FILLED) Postdoctoral Fellow – Therapeutic Genetics                                                                            

We are seeking a postdoctoral fellow 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.

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 management, 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, flow cytometry, metabolic and genomic analyses. Our lab is equipped with dedicated instruments to assess neuromuscular functions in small animals.

Qualifications:

Candidate must have (or be near to completing) a Ph.D., 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 a 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: dwi.kemaladewi@chp.edu.