The major objective of this proposal is to enable Dr. Timothy Gershon to develop an academic career that emphasizes translational laboratory investigation focusing basic neuro-developmental research techniques on problems encountered in his clinical work in Pediatric Neuro-oncology. Specifically, Dr. Gershon will focus on the pathogenesis of medulloblastoma and the development of novel, biologically-based anti-tumor therapy. Dr. Gershon will be mentored at the University of North Carolina (UNC), Chapel Hill where he began a tenure-track faculty position on July 31st, 2009. The primary mentor, Mohanish Deshmukh, Ph.D., will head this K08 mentorship program. Dr. Deshmukh is a leading expert in the regulation of apoptosis in neural development and has recently focused on the evasion of apoptosis in brain tumors. Dr. Deshmukh has a strong track record of publications, funding, and mentoring young investigators. He has developed a comprehensive mentoring plan for Dr. Gershon, primarily focused on developing experimental expertise in the use of genetically engineered mice, and the molecular dissection of apoptotic and metabolic processes. Research will focus on disruptions of cerebella neurogenesis that promote medulloblastoma formation from proliferating neural progenitors. Medulloblastoma is the most common malignant brain tumor in children and it arises in humans and mice from cerebella granule neuron progenitors. Using mice genetically engineered to be medulloblastoma-prone and apoptosis-deficient, Dr. Gershon has developed preliminary data for a highly novel hypothesis: that aerobic glycolysis and evasion of apoptosis are interrelated processes, integral to normal neurogenesis and co-opted in medulloblastoma. Through his Specific Aims, Dr. Gershon will test this hypothesis and its therapeutic implication, developing inhibition of glycolysis as an innovative treatment for medulloblastoma. To maximize his training experience, Dr. Gershon has assembled a UNC scientific advisory committee comprised of Dr. William Snider, Dr. Albert Baldwin and Dr. Matt Ewend. Meeting weekly with Dr. Deshmukh and quarterly with the advisory committee, Dr. Gershon will have continuous opportunity to gain feedback and advice from experienced experts in Neuroscience, Cancer Biology and Neuro-oncology. This expert oversight will enable the candidate to combine what he has previously learned and accomplished with a detailed and highly focused practical research experience that adapts a neuroscience approach to medulloblastoma. The mentorship, didactics, and research proposal along with the academic and research infrastructure provided by UNC will ensure the candidate's successful transition to an NIH-funded independent investigator.

Public Health Relevance

Medulloblastoma is the most common malignant brain tumor of children. This tumor arises from dysregulation of the cerebella growth that normally occurs in the first year of life. In this project, we will investigate how cerebella growth is controlled, inorder to gain new insight into how medulloblastoma may be treated, and we will test a novel treatment for medulloblastoma that was suggested by our preliminary studies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Clinical Investigator Award (CIA) (K08)
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NST-2 Subcommittee (NST)
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Fountain, Jane W
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
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Crowther, Andrew J; Ocasio, Jennifer K; Fang, Fang et al. (2016) Radiation Sensitivity in a Preclinical Mouse Model of Medulloblastoma Relies on the Function of the Intrinsic Apoptotic Pathway. Cancer Res 76:3211-23
Tech, Katherine; Gershon, Timothy R (2015) Energy metabolism in neurodevelopment and medulloblastoma. Transl Pediatr 4:12-9
Knight, E R W; Patel, E Y; Flowers, C A et al. (2015) ASC deficiency suppresses proliferation and prevents medulloblastoma incidence. Oncogene 34:394-402
Tech, Katherine; Deshmukh, Mohanish; Gershon, Timothy R (2015) Adaptations of energy metabolism during cerebellar neurogenesis are co-opted in medulloblastoma. Cancer Lett 356:268-72
Williams, Scott E; Garcia, Idoia; Crowther, Andrew J et al. (2015) Aspm sustains postnatal cerebellar neurogenesis and medulloblastoma growth in mice. Development 142:3921-32
Gershon, Timothy R; Crowther, Andrew J; Liu, Hedi et al. (2013) Cerebellar granule neuron progenitors are the source of Hk2 in the postnatal cerebellum. Cancer Metab 1:15
Crowther, Andrew J; Gama, Vivian; Bevilacqua, Ariana et al. (2013) Tonic activation of Bax primes neural progenitors for rapid apoptosis through a mechanism preserved in medulloblastoma. J Neurosci 33:18098-108
Garcia, I; Crowther, A J; Gama, V et al. (2013) Bax deficiency prolongs cerebellar neurogenesis, accelerates medulloblastoma formation and paradoxically increases both malignancy and differentiation. Oncogene 32:2304-14
Gershon, Timothy R; Crowther, Andrew J; Tikunov, Andrey et al. (2013) Hexokinase-2-mediated aerobic glycolysis is integral to cerebellar neurogenesis and pathogenesis of medulloblastoma. Cancer Metab 1: