Glioblastoma is a deadly and debilitating disease. Lacking effective treatment modalities, it has a 10- year mortality of nearly 100%. In order to understand this complex and highly heterogeneous tumor, it is critical that we develop tools that can measure individual cell populations within it. The Candidate proposes the use of ribosome profiling to identify the translational landscape within specific cellular populations of a murine RiboTag glioma model which recapitulates the human proneural glioma subtype. By molecularly dissecting the tumor through IP of markers associated with transformed cells and normoxic conditions, we can identify alterations in translation across multiple cellular subpopulations. Furthermore, by utilizing pRPS6 as a marker, we can shed light on this translationally important downstream effector of the mTOR pathway. In short, we aim 1) to identify phopsho-RPS6- associated transcripts in different cellular contexts and determine the impact of RPS6 phosphorylation on ribosome positioning and translation in cultured cells, 2) to dissect the normoxic and hypoxic populations of transformed cells in glioma tissue and determine the key pathways and potential therapeutic targets that differentiate them using ribosome profiling. These experiments will not only shed light on an important signaling molecule involved in neural development, invasion, proliferation, and metastasis, but could potentially uncover novel therapeutic targets and lead to enhanced treatments for this disease.

Public Health Relevance

A particular issue in the treatment and study of glioma is the high level of cellular heterogeneity found within. By utilizing a method which will allow for signa and cell-type specific selection, this project will allow significant gains to be made in understanding the translational activity of specific populations within glioma as well as the translational effects of a critical molecule in a pathway essential for tumor proliferation and invasion. This understanding may ultimately allow for new therapies and treatment paradigms to be developed in order to combat this insidious and deadly disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS089106-03
Application #
9095461
Study Section
NST-2 Subcommittee (NST)
Program Officer
Fountain, Jane W
Project Start
2014-07-01
Project End
2017-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Biochemistry
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Hornstein, Nicholas; Torres, Daniela; Das Sharma, Sohani et al. (2016) Ligation-free ribosome profiling of cell type-specific translation in the brain. Genome Biol 17:149
Gonzalez, Christian; Sims, Jennifer S; Hornstein, Nicholas et al. (2014) Ribosome profiling reveals a cell-type-specific translational landscape in brain tumors. J Neurosci 34:10924-36