The Tomita laboratory (Pediatric Neurosurgery Laboratory) at Stanley Manne Children’s Research Institute is committed to studying and treating pediatric neurosurgical diseases or abnormalities which include but are not limited to Spina Bifida, hydrocephalus and pediatric brain tumors. We have launched a project on stroke-induced inflammation as an offshoot of our prior work that demonstrated the role of folic acid during embryonic development in the creation of certain microRNAs that may potentially be involved in stroke-mediated inflammation.
Current Research Projects
Prevention and Repair of Spina Bifida in Utero
We have identified the mechanism by which folic acid impacts neural tube development in a mouse model of neural tube defect or Myelomengiocele (MM). We have applied this knowledge to understand MM in humans. Using amniotic fluid and amniotic fluid stem cells from women with neural tube-affected pregnancies, we discovered that the expression of certain histone marks (modified nuclear proteins) targeted by folic acid treatment was higher in neural tube affected pregnancies than normal pregnancies. In addition, our team found that certain markers that are present in the amniotic fluid of the women with neural tube defect-affected pregnancies are also present in their blood serum, thereby giving us a diagnostic tool to detect MM and devise patient specific treatment strategies. The long-term goal is to find a repair mechanism for MM after it has been diagnosed in the second trimester of pregnancy. We have recently embarked upon an ambitious project to develop a minimally invasive approach for the prenatal repair of MM using repair molecules and stem cells to close the neural tube.
Novel Functions of Folate Receptor alpha (FRα) in Central Nervous System Development and Disease
The protein FRα is critical for embryonic development. Disruption of both FRα alleles in mice results in a range of malformations and is lethal to the embryos at the time of neural tube closure. A recent body of evidence emphasizes its role in neural tube defects, cerebral folate deficiency, autism and autism spectrum disorders. Circulating autoantibodies against FRα and cerebral folate deficiency appear to play a crucial role in the cause and pathogenesis of a subgroup of autism spectrum disorders with co-existing neurological deficits. Since FRα is known to be overexpressed in cancer cells, it has found a novel role in cancer diagnosis and treatment. Our lab recently discovered a novel role of FRα as a transcription factor, providing insights into developmental mechanisms associated with FA. It also provides an exciting new avenue to explore treatment strategies for diseases associated with FA deficiency, FRα misregulation, and cancers that overexpress FRα.
MicroRNA Based Molecular Shunt to Treat Hydrocephalus
This study examines the possibility of exploiting miRNAs as natural endogenous modulators of aquaporin channels; junction associated proteins and different matrix metalloproteases expression, which are drastically changed during hydrocephalus. This study is expected to provide a diagnostic as well as therapeutic intervention strategy into treating hydrocephalus using small molecules, thereby obviating the need of a mechanical shunt for hydrocephalic individuals.
Nanodiamond-Chemotherapy Drug Complexes to Treat Malignant Brain Tumors
We are investigating ways to improve chemotherapeutic drug delivery through the use of nanodiamond therapies. The hypothesis is that these microscopic particles can be retained longer within a tumor cell, thus extending the benefit of the chemotherapy drug. We have shown that nanodiamonds markedly enhanced the absorption and retention of the drug doxorubicin in glioma cell lines, and localize its toxicity in a rodent model. Moreover, it is significantly more efficient at killing tumor cells than regular doxorubicin. Conjugating nanodiamonds with another chemotherapy drug, cisplatin is highly effective in the treatment of solid tumors. We believe that using nanodiamonds to deliver cisplatin will lower the drug’s systematic distribution and side effects.
Elucidating the Relationship Between Global Histone Modifications and Carcinogenesis in Pediatric Brain Tumors
Brain tumors are common in children. Despite advances in treatment protocols, clinical results continue to be disappointing. In recent years, substantial progress has been made in understanding the role of epigenetics, including histone modifications, in the pathogenesis of brain tumors. Methylation of histone 3 on lysine 4 (H3K4) plays a critical role in transcriptional activation in a variety of eukaryotic species. The functional impact of different degrees of H3K4 methylation is poorly understood. A strong positive correlation exists between high levels of H3K4 trimethylation (H3K4me3), transcription rates and active polymerase II occupancy. Recent studies have shown that H3K4me3 plays a role in determining the course of various types of human cancers, including brain tumors. We are investigating H3K4 methylation and other global histone modifications in pediatric brain tumors in an effort to correlate these modification patterns, as well as their associated enzymes to tumor behavior, and eventually histone marks for clinical diagnosis, treatment and prognosis prediction.
Animal (Zebrafish) Model of AT/RT
Atypical Teratoid Rhabdoid tumors (AT/RT) are among the most aggressive and untreatable tumors in pediatric oncology, affecting young children. Treatment involves highly toxic multidrug therapy with poor clinical response. To gain a better understanding of AT/RT biology with the ultimate goal to find a cure for this dreadful disease, our efforts are comprised of genomic studies of AT/RT patient tumor samples, genetic analyses of AT/RT families and development of a zebrafish model of the disease, which will enable us to screen numerous drugs for effectiveness vs. toxicity in a short period of time. We have already identified a list of molecules targeted by commercially available drugs to be tested upon completion and proper validation of the model. Visit the iSTAR AT/RT Laboratory.
On another front, we are developing a molecular test that can identify pediatric low-grade gliomas that are likely to regress spontaneously. This test will allow doctors to treat only tumors that have the potential for recurrence, avoiding unnecessary toxicity to many children whose tumors can regress spontaneously.
List of publications indexed in PubMed by the Tomita Laboratory
Guifa Xi, MD, PhD, Research Scientist
Mohammed Rizwan Siddiqui, PhD, Research Scientist
Barbara Mania Farnell, PhD, Visiting Scholar
Vineet Mohanty, MS, Research Associate
Simone Sredni, MD, PhD, Research Associate Professor