My project will investigate the mechanisms underlying cerebellar growth failure and apply this understanding to medulloblastoma, a tumor of excess cerebellar growth. These two interrelated conditions are both important sources of medical illness in children. Cerebellar development depends on the regulated growth of a population of neuronal precursor cells called cerebellar granule neuron progenitors (CGNPs). Failure of these cells to expand their population leads to cerebellar hypoplasia, as seen in the congenital disorder Seckel syndrome. In contrast, excessive proliferation of CGNPs predisposes to medulloblastoma, the most common malignant brain tumor of childhood. Although mutation of the DNA repair protein ATR is known to cause Seckel syndrome, the mechanism through which ATR deficiency results in neurodevelopmental defects is still not fully understood. The hypo-plastic phenotype of Seckel syndrome, however, suggests that ATR disruption may be exploited in the treatment of the hyper-plastic disorder medulloblastoma. The goal of this Kirschstein-NRSA individual fellowship (F30) project is to delineate why ATR is required for cerebellar growth and whether ATR disruption may be used in medulloblastoma treatment. I have found that conditional deletion of ATR in the mouse cerebellum causes widespread DNA damage and cell death in CGNPs, resulting in the formation of small, disorganized cerebella. However, the mechanism by which ATR deficiency leads to CGNP damage and death, and consequently cerebellar hypoplasia, is still unclear. My experiments will use tissues and cells from ATR-deficient mice to reveal where in the cell cycle DNA damage accumulates in CGNPs in response to loss of ATR (Specific Aim 1), and how CGNPs die when they lack ATR (Specific Aim 2). Delineating the mechanism by which CGNPs are damaged and die in response to ATR loss will advance the understanding of Seckel syndrome. CGNP requirement for ATR, as revealed by Seckel syndrome and as seen in ATR-deficient mice, suggests that ATR may be targeted as a novel therapy for medulloblastoma. My preliminary work shows that genetic deletion of ATR during early development in medulloblastoma-prone mice has a profound anti-tumor effect. I thus propose in Specific Aim 3 to determine if deletion of ATR after the point of tumor formation will have a similar anti-tumor effect. My findings will advance cancer treatment by testing the value of targeting ATR in treating medulloblastoma. The proposed training and research plans outlined in this NIH F30 fellowship application will provide me with outstanding education in the areas of cell physiology, neuroscience, cancer biology, and molecular pharmaceutics, and promote my professional development toward a career as a physician-scientist.
Cerebellar hypoplasia and medulloblastoma are severe childhood neurological disorders that both result from failed regulation of cerebellar development. Deficiency of the protein ATR causes cerebellar hypo-plasia associated with the congenital disorder Seckel syndrome, suggesting that ATR may be targeted to treat the pediatric tumor medulloblastoma, a condition of cerebellar hyper-plasia. The studies outlined in this proposal seek to reveal the mechanism by which ATR loss produces cerebellar pathology and to apply this understanding towards using ATR inhibition as a novel means to treat medulloblastoma.
|Lang, Patrick Y; Gershon, Timothy R (2018) A New Way to Treat Brain Tumors: Targeting Proteins Coded by Microcephaly Genes?: Brain tumors and microcephaly arise from opposing derangements regulating progenitor growth. Drivers of microcephaly could be attractive brain tumor targets. Bioessays 40:e1700243|
|Lang, Patrick Y; Nanjangud, Gouri J; Sokolsky-Papkov, Marina et al. (2016) ATR maintains chromosomal integrity during postnatal cerebellar neurogenesis and is required for medulloblastoma formation. Development 143:4038-4052|