The central nervous system group within the Center for Genetic Medicine Research works closely with investigators in the Center for Neuroscience Research and the Center for Cancer and Immunology Research. Key investigators are Adeline Vanderver, MD, who leads international efforts focused on understanding childhood white matter disorders, Susan Knoblach, PhD, on spinal cord trauma and ALS, Javad Nazarian, PhD, on pediatric brain tumors, and Yetrib Hathout, PhD, working on neurofibromatosis.
Brain tumors are the leading cause of cancer death in children. More than 50 percent of pediatric brainstem tumors are brainstem gliomas (BSG). These are classified into four categories on the basis of anatomic location and radiographic appearance: diffuse, focal intrinsic, focal exophytic, and cervicomedullary. The most common form is diffuse intrinsic pontine glioma (DIPG), accounting for 80 percent of all brainstem gliomas. Little is known about the molecular biology of DIPG compared to other gliomas, making treatment challenging.
Our group is part of the Mid-Atlantic DIPG Consortium (MADC), which also includes the National Cancer Institute (NCI), and Johns Hopkins Medical Center. Dr. Javad Nazarian’s multidisciplinary team of experts which includes neurologists, neurosurgeons, bioengineers and oncologists have been involved in generating the complete protein profile of CSF from children with brain tumors. This group works together with Rohan Fernandes, PhD, MS, to bioengineer nanoparticles for treating brain cancers.
The group has also generated the complete protein profile of the only genetically engineered (PDGFb induced) murine model of brainstem gliomas. Significantly dysregulated proteins have been identified and are tested in autopsied human brainstem glioma specimens. The murine model is being used to test therapeutics and in vivo validation of identified target molecules.
Dr. Yetrib Hathout is using proteomics techniques to advance our understanding of the molecular mechanisms of the invasive behavior of glioblastoma multiform, a devastating brain tumor that often has very poor prognosis. Dr. Hathout used stable isotope labeling by amino acid in cell culture to define novel secreted proteins that might explain the invasive behavior of glioblastoma (Formolo et al 2011).
Dr. Hathout has also been involved on several collaborative projects using proteomics and mass spectrometry approach to define novel CSF biomarkers associated with meduloblastoma (Rajagopal et al. 2011), and leukodystrophies (Brown et al. 2011).
The Myelin Disorders Program at Children's National is a multidisciplinary clinical and bench research program studying inherited disorders of the cerebral white matter or leukodystrophies. The program includes an integrated clinical program with a Myelin Disorders Clinic staffed by neurologists, pediatricians, rehabilitation physicians and genetic counselors. Our group studies vanishing white matter (VWM) disease, also known as Childhood Onset Ataxia and Central Nervous System Hypomyelination (CACH) or eIF2B related disorder. This is a disorder of glial cell endoplasmic (ER) stress regulation caused by mutations in one of five genes encoding the eIF2B complex. We also study Aicardi Goutières syndrome (AGS), an inherited disorder of innate cellular immunity that primarily affects the central nervous system, resulting in severe neurologic disability. As part of an international consortium, we study the natural history and phenotype of patients with AGS.
In about 50 percent of patients with leukodystrophy, the root cause remains unknown. This represents a significant burden of disease, since patients with no known diagnosis continue to undergo extensive and often invasive testing, and in addition have limited options for therapeutic management, or genetic counseling. In addition, these subjects represent a missed opportunity to better understand causes of glial cell dysfunction, and therefore increase our knowledge of myelin homeostasis. To this end, we have developed a national consortium to identify and diagnose patients with unsolved leukodystrophies via a virtual second opinion program and biorepository. Wherever possible, a known diagnosis is established by a consortium of experts in the leukodystrophy field, reviewing virtual records and, if necessary, by direct clinical evaluation in a Center of Excellence in Leukodystrophy and Leukoencephalopathy (CELL). Those patients remaining without a diagnosis are retained for participation in the search for new nosologic entities and genetic causes of leukodystrophy using state of the art genomic and proteomic applications.
Together with the Division of Pediatric Neuropsychology and the SCORE (Safe Concussion Outcome, Recovery and Education) clinic at Children's National, we are studying biomarkers of mild concussion in high school athletes. We are investigating whether nucleic acids and/or proteins released into the bloodstream or saliva after injury may be useful indicators of how much brain damage has occurred. We are also creating a biorepository of DNA from children that have sustained traumatic brain injury, to begin to understand genetic variations that may influence how a person responds to a given injury. In addition, we are developing laboratory models of mild concussion to elucidate the mechanisms behind the injury response and identify new intervention strategies to enhance recovery.
Faculty with interests in brain disorders include:
Brain tumors and neurofibromatosis
Traumatic brain injury
- Susan Knoblach, PhD
- Joseph Devaney, PhD