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Breakefield awarded $5.8 million to study tumors

DF/HCC member Xandra Breakefield, PhD (MGH) will receive approximately $5.8 million in total costs over five years to study the genetic and cellular factors contributing to the formation and progression of benign tumors in the nervous system. Breakefield and colleagues have successfully renewed this funding from the National Institute of Neurological Disorders and Stroke (NINDS). The P01, entitled “Molecular Genetics of Inherited Neurological Diseases,” consists of three projects:

Molecular genetics of meningioma and NF-related disorders
James Gusella, PhD(MGH)
Gusella and colleagues will identify the genes responsible for initiation of meningiomas (which account for 25 percent of brain tumors and cause significant morbidity) and for elaboration of specific meningioma phenotypes not caused by loss of merlin function. Specific aims are to:

  • Use molecular genetic strategies to identify genes that are responsible for the initiation of meningiomas in which merlin expression persists or for the progression of meningiomas
  • Use the comparison between meningioma cells and matching normal cells of origin, arachnoidal cells, as a means of identifying additional genes contributing to the phenotype of merlin-negative meningiomas
  • In conjunction with the other two projects and the cores, use the whole genome dosage analysis to compare tumors from the phakomatoses


Mouse brain models of tuberous sclerosis

David Kwiatkowski, MD, PhD (BWH)
In project two, Kwiatkowksi and colleagues will study two genes, TSC1 and TSC2. Both genes are recognized to cause tuberous sclerosis, an autosomal dominant tumor suppressor gene syndrome characterized by development of distinctive benign tumors and malformations in multiple organ systems. Specific aims are to:

  • Analyze the effects of neuronal loss of TSC1 in vivo
  • Generate a brain model of TSC with giant cells using a regulatable nestin promoter
  • Conduct signaling and pathogenesis studies on brain models


Vector query and therapy for TSC and NF2 lesions
Xandra Breakefield, PhD and Miguel Sena-Esteves, PhD (MGH)  
In the final project, Breakefield, Sena-Esteves, and colleagues will use adeno-associated virus (AAV) to elucidate cells of origin and create mouse models of brain lesions in TSC and schwannomas in neurofibromatosis type 2 (NF2). They will also use AAV and herpes simplex virus amplicon vectors to explore treatment paradigms for these lesions. Specific aims are to:

  • Determine the contribution of neuroprecursor cells to brain lesions in a mouse model of TSC
  • Evaluate the ability of AAV vectors encoding hamartin to correct the neurologic phenotype of TSC1 c/c x synapsin-1-Cre offspring as compared to rapamycin treatment
  • Identify disregulated microRNAs in human meningioma tumors relative to merlin status and to normal cells of origin
  • Develop a model for spontaneous NF2-null schwannomas, and evaluate the ability of HSV amplicon vectors expressing an apoptopic protein to achieve regression of implanted human schwannomas tumors