Analysis of Toxicant-Induced Translational Control Through Codon-Usage Bias in Lung Cancer
Abstract
The proposed project addresses the Lung Cancer Research Program Area of Emphasis ?Understand contributors to lung cancer development other than tobacco.? Lung cancer is caused by inherited mutations and induced mutations, including mutations induced by exposure to chemicals and particulates in air pollution. Military personnel are at risk of such exposures during their deployment, such as the intense air pollution in many cities around the world and the smoke and fumes encountered during combat operations. These mutations lead to the loss of control of cell growth and replication that underlies cancer, with many normal lung cell processes disrupted in cancer cells, including the timely and appropriate expression of genes. The proposed studies aim to understand how a novel mechanism controlling gene expression is disrupted in lung cancer cells. The mechanism involves ?reprogramming? of dozens of building blocks of the RNA molecules that represent copies of genes and that are translated into proteins that represent some of the normal functioning components of the lung cell. This reprogramming, which occurs both as a result of stresses experienced by the cells and hypothetically as a result of cancer mutations, causes selective translation of both stress response genes and possibly of cancer-related genes that possess a second genetic code that matches the reprogrammed RNA molecules. The proposed studies test these models by defining the role of this novel translational control mechanism in normal lung cells and in lung cancer cells. This model for control of gene expression has the potential for impact in many areas, including (1) revealing important new mechanisms that link lung cell exposures to mutations and cancer, (2) revealing mechanisms that underlie the behavior of lung cancer cells and may represent new targets for anti-cancer drugs, and (3) revealing mechanisms that lead to resistance to anti-cancer drugs, with these mechanisms targeted for development of resistance-reversing adjuvant cancer therapies. Although this project does not have an immediate and direct clinical outcome, the discoveries made in this project will advance our understanding of causes of lung cancer and reveal new targets for development of anti-cancer drugs, which would occur within a decade after the end of the project. Military personnel will benefit significantly from these outcomes given their atypical pulmonary exposures encountered during deployment and combat operations.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710185
Entities
People
- Ahmed Fazly
Organizations
- Massachusetts Institute of Technology
- United States Army