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Research at Mass General
James A. Walker, PhD Principal Investigator, Center for Genomic Medicine, Massachusetts General Hospital Assistant Professor of Neurology, Harvard Medical School Associate Member of the Broad Institute
The Walker Laboratory at Massachusetts General Hospital focuses on the tumor-suppressor syndromes, neurofibromatosis type 1 (NF1) and schwannomatosis. Using a combination of genetic, molecular and biochemical approaches, we aim to identify new therapeutic targets for these diseases.
Neurofibromatosis type 1 (NF1) is an autosomal dominantly inherited tumor predisposition syndrome with an incidence of one in 3,000–4,000 people with no effective therapies currently. NF1 is a chronic multisystem disorder affecting many different tissues. Most adults with NF1 develop neurofibromas - benign, but often disfiguring, peripheral nerve associated tumors. About 10% of NF1 patients develop malignant peripheral nerve sheath tumors (MPNSTs), which carry a poor prognosis and are often fatal.
The NF1 gene encodes the protein neurofibromin, which functions as a negative regulator of RAS. Due to cell-specific complexities of RAS signaling, therapeutic approaches for NF1 will likely have to focus on a particular tissue and manifestation of the disease.
Familial schwannomatosis is a late-onset tumor predisposition disorder - clinically and genetically distinct from NF1 and NF2. Affecting 1 in 40,000 individuals, the disease is characterized by multiple peripheral nerve tumors, called schwannomas, and a predisposition to other nervous system tumors including meningiomas. Patients with schwannomatosis overwhelmingly present with intractable pain. Mutations in three genes are known to be involved in schwannomatosis:
Currently, there are no effective therapies to prevent schwannoma formation or relieve schwannomatosis pain.
James A. Walker, PhD Center for Genomic Medicine, Massachusetts General Hospital Assistant Professor of Neurology, Harvard Medical School Associate Member of the Broad Institute
Theodosia Charitou, PhD Postdoctoral Fellow
Brittany Leger, BS Research Technician
Samuel Ching Undergraduate placement student (Bath University, UK)
Rebecca Drake Undergraduate placement student (Exeter University, UK)
Timothy O’Meara Undergraduate, Harvard University
Modeling signaling networks of NF1-deficient Schwann cells and plexiform neurofibromas using mass spectrometry-based proteomics
Gary Johnson, PhD, UNC School of Medicine, UNC Chapel HillWilli Haas, PhD, Mass General Cancer Center
NF1 genotype-phenotype relationships: Functional analysis of pathogenic mutations in neurofibromatosis type 1 (NF1)
Alexey Veraksa, PhD, University of Massachusetts, BostonStephen Haggarty, PhD, Mass General Center for Genomic Medicine
Identification of genetic modifiers of NF1 using a Drosophila model
Developing a schwannomatosis cell model using CRISPR/Cas9 genome editing
Justin T. Jordan, MD, Mass General Pappas Center for Neuro-OncologyScott R. Plotkin, MD, PhD, Mass General Pappas Center for Neuro-OncologyAnat Stemmer-Rachamimov, MD, PhD, Mass General Department of PathologyVijaya Ramesh, PhD, Mass General Center for Genomic Medicine
Role of huntingtin in Drosophila brain development
Lee Fradkin, PhD, University of Massachusetts Medical SchoolJean-Maurice Dura, PhD, Institute of Human Genetics, CNRS
Molecular and cellular networks influencing sleep behavior in Drosophila
Richa Saxena, PhD, Mass General Center for Genomic Medicine Shubhroz Gill, PhD, Broad Institute Stuart Schreiber, PhD, Broad Institute Girish Melkani, PhD, San Diego State University
Development of synthetic gene drives using small molecules
Amit Choudhary, PhD, Broad InstituteShubhroz Gill, PhD, Broad Institute
To inquire regarding positions in the laboratory, please send an email with a brief cover letter and CV to:
James A. Walker, PhD Center for Genomic Medicine Massachusetts General Hospital Simches Research Building 185 Cambridge Street Boston, MA 02114
Walker, J.A. and Upadhyaya, M. (2018) Emerging therapeutic targets for neurofibromatosis type 1. Expert Opin. Ther. Targets. May;22(5):419-437
Jordan, J.T., Smith, M.J., Walker, J.A., Erdin, S., Merker, V., Cai, W., Harris, G.J., Miriam A. Bredella, M.A., Suuberg, A., Gusella, J.F. and Plotkin, S.R. (2018) Capture-Based Sequencing and Whole-Body MRI for Genotype-Phenotype Correlations in Schwannomatosis. Medicine. Feb;97(5):e9717.
Perea, D., Guiu, J., Hudry, B., Hadjieconomou, D., Hoyer, N., Natarajan, D., Kallijärvi, J., Walker, J.A., Soba, P., Thapar, N., Burns, A.J., Jensen, K.B. and Miguel-Aliaga, I. (2017) A new enteric role for the Ret tyrosine kinase receptor in somatic stem cells of the adult intestinal epithelium. EMBO J. Oct 16;36(20):3029-3045.
Parasuraman, P., Mulligan, P., Walker, J.A., Li, B., Boukhali, M., Haas, W. and Bernards, A. (2016) Interaction of p190A RhoGAP with eIF3A and other translation preinitiation factors suggests a role in protein biosynthesis. J. Biol. Chem. 292(7):2679-2689.
Dietz, K.N., Di Stefano, L., Maher, R.C., Zhu, H., MacDonald, M.E., Gusella, J. F. and Walker, J.A. (2015) Huntingtin influences chromatin regulation in Drosophila. Hum. Mol. Genet. 24(2):330-45
Hutchinson, C.V., Walker, J.A. and Davidson, C. (2014) Oestrogen, ocular function and low-level vision: a review. J Endocrinol. 223(2):R9-R18.
Walker, J.A. and Bernards, A. (2014) A Drosophila screen identifies neurofibromatosis-1 genetic modifiers involved in systemic and synaptic growth. Rare Diseases. 2(1): e28341-1-4.
Walker, J.A., Gouzi, J.Y., Long, J.B., Huang, S., Maher, R.C., Xia, H., Khalil, K., Ray, A., Van Vactor, D., Bernards, R. and Bernards, A. (2013) Genetic and Functional Studies Implicate Synaptic Overgrowth and Ring Gland cAMP/PKA Signaling defects in the Drosophila Neurofibromatosis-1 Growth Deficiency. PLoS Genet. 9(11): e1003958.
Walker, J.A., Gouzi, J.Y. and Bernards, A. (2013) Drosophila: An invertebrate model of NF1. In Molecular and Cellular Biology of Neurofibromatosis Type 1” Eds: Upadhyaya, M. and Cooper, D.N. Springer Verlag.
Contact the Walker Laboratory at Massachusetts General Hospital:
James A. Walker, PhD Center for Genomic Medicine Massachusetts General Hospital Simches Research Building, Room 5600 185 Cambridge Street Boston, MA 02114
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